Stichodactyla toxin: Difference between revisions

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	}

ShK domain-like
ShK domain-like
	Rainbow colored cartoon diagram (N-terminus = blue, C-terminus = red) of an NMR solution structure of the ShK toxin. Sidechains of cysteine residues involved in disulfide linkages are displayed as sticks and the sulfur atoms in these links are colored yellow.
Identifiers
Symbol	ShK
Pfam	PF01549
InterPro	IPR003582
SMART	SM00254
SCOP2	1roo / SCOPe / SUPFAM
TCDB	8.B.14
OPM superfamily	475
OPM protein	2lg4
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary
PDB	}

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Stichodactyla toxin (ShK) is a 35-residue basic peptide from the sea anemone Stichodactyla helianthus that blocks a number of potassium channels. An analogue of ShK called ShK-186 or Dalazatide is in human trials as a therapeutic for autoimmune diseases.

History

Stichodactyla helianthus is a species of sea anemone (Phylum: Cnidaria) belonging to the family Stichodactylidae. Helianthus comes from the Greek words Helios meaning sun, and anthos meaning flower, which corresponds to S. helianthus common name "sun anemone". It is sessile and uses potent neurotoxins for defense against its primary predator, the spiny lobster.^[2] The venom contains, among other components, numerous ion channel-blocking peptides. In 1995, a group led by Olga Castaneda and Evert Karlsson isolated ShK, a potassium channel-blocking 35-residue peptide from S. helianthus.^[3] The same year, William Kem and his collaborator Michael Pennington synthesized and folded ShK, and showed it blocked neuronal and lymphocyte voltage-dependent potassium channels.^[4] In 1996, Ray Norton determined the three-dimensional structure of ShK.^[5] In 2005-2006, George Chandy, Christine Beeton and Michael Pennington developed ShK-170 and ShK-186, selective blockers of K_v1.3.^[6]^[7] ShK-186, now called Dalazatide, was advanced to human trials in 2015-2017 by Shawn Iadonato and Eric Tarcha, as the first-in-man K_v1.3 blocker for autoimmune disease.^[8]References used only in figure 1^[9]^[10]^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]^[19]^[20]^[21]

Structure

ShK is cross-linked by three disulfide bridges: Cys3-Cys35, Cys12-Cys28, and Cys17-Cys32. The solution structure of ShK reveals two short α-helices comprising residues 14-19 and 21-24; the N-terminal eight residues adopt an extended conformation, followed by a pair of interlocking turns that resemble a 3₁₀ helix; the C-terminal Cys35 residue forms a nearly head-to-tail cyclic structure through a disulfide bond with Cys3.^[22]^[23]^[24]^[25]^[26]^[27]

Phylogenetic relationships of ShK and ShK domains

The SMART database at the EMBL, as of May 2018,^[28] lists 3345 protein domains with structural resemblance to ShK in 1797 proteins (1 to 8 domains/protein), many in the worm Caenorhabditis elegans and venomous snakes.^[29]^[30]^[31]^[32]^[33] The majority of these domains are in metallopeptidases, whereas others are in prolyl 4-hydroxylases, tyrosinases, peroxidases, oxidoreductases, or proteins containing epidermal growth factor-like domains, thrombospondin-type repeats, or trypsin-like serine protease domains.^[29]^[30]^[31]^[32]^[33] The only human proteins containing ShK-like domains are MMP-23 (matrix metalloprotease 23) and MFAP-2 (microfibril-associated glycoprotein 2).^[29]^[30]^[31]^[32]^[33]

Channel targets

The ShK peptide blocks potassium (K⁺) ion channels K_v1.1, K_v1.3, K_v1.6, K_v3.2 and K_Ca3.1 with nanomolar to picomolar potency, and has no effect on the HERG (K_v11.1) cardiac potassium channel.^[34]^[35] The neuronal K_v1.1 channel and the T lymphocyte K_v1.3 channel are most potently inhibited by ShK.^{^[36]}

Binding configuration in K⁺ channels

ShK and its analogues are blockers of the channel pore. They bind to all four subunits in the K⁺ channel tetramer by interacting with the shallow vestibule at the outer entrance to the channel pore.^[37]^[38]^[39]^[40]^[41]^[42]^[43] These peptides are anchored in the external vestibule by two key interactions. The first is Lys22, which protrudes into and occludes the channel’s pore like a "cork in a bottle" and blocks the passage of potassium ions through the channel pore.^[38]^[44]^[42]^[43] The second is the neighboring Tyr23, which together with Lys22 forms a “functional dyad” required for channel block.^[38]^[39]^[42]^[44]^[43] Many K⁺ channel-blocking peptides contain such a dyad of a lysine and a neighboring aromatic or aliphatic residue.^[43]^[45] Some K⁺ channel-blocking peptides lack the functional dyad, but even in these peptides a lysine physically blocks the channel, regardless of the position of the lysine in the peptide sequence.^[46] Additional interactions anchor ShK and its analogues in the external vestibule and contribute to potency and selectivity.^[38]^[39]^[42]^[44]^[43] For example, Arg11 and Arg29 in ShK interact with two Asp386 residues in adjacent subunits in the mouse K_v1.3 external vestibule (corresponds to Asp433 in human K_v1.3).^[38]^[39]^[42]^[44]^[43]

IC₅₀ values for block of potassium channels by ShK and related peptides. ND = not done.
Channel	ShK(IC₅₀)	ShK-186 (IC₅₀)	ShK-192 (IC₅₀)	ShK-EWSS (IC₅₀)	ShK-F6CA(IC₅₀)	ShK-198(IC₅₀)	MMP-23 ShK domain(IC₅₀)
K_v1.1	16-28 pM	7 nM	22 nM	5.4 nM	4 nM	159 pM	49 μM
K_v1.2	10 nM	48 nM	ND	>100 nM	>100 nM	ND	>100 μM
K_v1.3	10-16 pM	70 pM	140 pM	34 pM	48 pM	41 pM	2.8 μM
K_v1.6	200 pM	18 nM	10.6 nM	ND	ND	ND	400 nM
K_v3.2	5 nM	20 nM	4.2 nM	ND	ND	ND	49 μM
K_Ca3.1	30 nM	115 nM	>100 nM	>100 nM	ND	ND	>100 μM

Analogues that block the Kv1.3 channel

Several ShK analogues have been generated to enhance specificity for the K_v1.3 channel over the neuronal K_v1.1 channel and other closely related channels.

ShK-Dap²²: This was the first analogue that showed some degree of specificity for K_v1.3. The pore-occluding lysine²² of ShK is replaced by diaminopropionic acid (Dap) in ShK-Dap²².^[47]^[48]^[49] Dap is a non-natural lysine analogue with a shorter side chain length (2.5 Å from C_α) than lysine (6.3 Å).^[50] Dap²² interacts with residues further out in the external vestibule in contrast to lysine²², which interacts with the channel’s selectivity filter.^[48] As a consequence, the orientations of ShK and ShK-Dap²² in the external vestibule are significantly different.^[48] ShK-Dap²² exhibits >20-fold selectivity for K_v1.3 over closely related channels in whole-cell patch clamp experiments,^[47] but in equilibrium binding assays it binds K_v1.1-K_v1.2 heterotetramers with almost the same potency as ShK, which is not predicted from the study of homotetrameric K_v1.1 or K_v1.2 channels.^[49]
ShK-F6CA: Attaching a fluorescein to the N-terminus of the peptide via a hydrophilic AEEA linker (2-aminoethoxy-2-ethoxy acetic acid; mini-PEG) resulted in a peptide, ShK-F6CA (fluorescein-6-carboxyl), with 100-fold specificity for K_v1.3 over K_v1.1 and related channels.^[51] Attachment of a tetramethyl-rhodamine or a biotin via the AEEA linker to ShK’s N-terminus did not increase specificity for K_v1.3 over K_v1.1.^[51] The enhanced specificity of ShK-F6CA might be explained by differences in charge: F6CA is negatively charged; tetramethylrhodamine is positively charged; and biotin is neutral.^[51] Subsequent studies with other analogues suggest that the negatively charged F6CA likely interacts with residues on the turret of the K_v1.3 channel as shown for ShK-192 and ShK-EWSS.^[52]^[53]

ShK-170, ShK-186, ShK-192 and ShK-EWSS: Based on ShK-F6CA additional analogues were made. Attaching a L-phosphotyrosine to the N-terminus of ShK via an AEEA linker resulted in a peptide, ShK-170, with 100-1000-fold specificity for K_v1.3 over related channels. ShK-186 [a.k.a. SL5; a.k.a. Dalazatide] is identical to ShK-170 except the C-terminal carboxyl is replaced by an amide. ShK-186 blocks K_v1.3 with an IC₅₀ of 69 pM and exhibits the same specificity for K_v1.3 over closely related channels as ShK-170.^[54] The L-phosphotyrosine of ShK-170 and ShK-186 rapidly gets dephosphorylated in vivo generating an analogue, ShK-198, with reduced specificity for K_v1.3.^[55]^[56]^[57] To overcome this problem, ShK-192 and ShK-EWSS were developed. In ShK-192, the N-terminal L-phosphotyrosine is replaced by a non-hydrolyzable para-phosphonophenylalanine (Ppa), and Met21 is replaced by the non-natural amino acid norleucine to avoid methionine oxidation.^[52]^[57] In ShK-EWSS, the AEEA linker and L-phosphotyrosine are replaced by the residues glutamic acid (E), tryptophan (W) and two serines (S).^[53] Both ShK-192 and ShK-EWSS are highly specific for K_v1.3 over related channels.

ShK-K18A: Docking and molecular dynamics simulations on K_v1.3 and K_v1.1 followed by umbrella sampling simulations, paved the way to the selective Kv1.3 inhibitor ShK-K18A.^[58]

ShK-related peptides in parasitic worms: AcK1, a 51-residue peptide from hookworms Ancylostoma caninum and Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from filarial worm Brugia malayi, adopt helical structures closely resembling ShK.^[59] AcK1 and BmK1 block K_v1.3 channels at nanomolar-micromolar concentrations, and they suppress rat effector memory T cells without affecting naïve and central memory T cell subsets.^[59] Further, they suppress IFN-g production by human T cells and they inhibit the delayed type hypersensitivity response caused by skin-homing effector memory T cells.^[59] Teladorsagia circumcincta is an economically-important parasite that infects sheep and goats. TcK6, a 90-residue protein with a C-terminal ShK-related domain, is upregulated during the mucosal dwelling larval stage of this parasite.^[60] TcK6 causes modest suppression of thapsigargin-triggered IFN-g production by sheep T cells, suggesting that the parasite use this protein for immune evasion by modulating mucosal T cells.^[60]

Extending circulating half-life

Due to their low molecular mass, ShK and its analogues are prone to rapid renal elimination. In rats, the half-life is ~6 min for ShK-186 and ~11 min for ShK-198, with a clearance rate of ~950 ml/kg·min.^[61] In monkeys, the half-life is ~12 min for ShK-186 and ~46 min for ShK-198, with a clearance rate of ~80 ml/kg·min.^[61]

PEGylation of ShK: Conjugation of polyethylene glycol (PEG) to ShK[Q16K], an ShK analogue, increased its molecular mass and thereby reduced renal clearance and extended plasma half-life to 15 h in mice and 64 h in cynomolgus monkeys.^[62] PEGylation can also decrease immunogenicity and protect a peptide from proteolysis and non-specific adsorption to inert surfaces. PEGylated ShK[Q16K] prevented adoptive-transfer experimental autoimmune encephalomyelitis in rats, a model for multiple sclerosis.^[62]

Conjugation of ShK to larger proteins: The circulating half-life of peptides can be prolonged by coupling them to larger proteins or protein domains.^[63]^[64]^[65] By screening a combinatorial ShK peptide library, novel analogues were identified, which when fused to the C-termini of IgG1-Fc retained picomolar potency, effectively suppressed in vivo delayed type hypersensitivity and exhibited a prolonged circulating half-life.^[66]

Prolonged effects despite rapid plasma clearance: SPECT/CT imaging studies with a ¹¹¹In-DOTA-conjugate of ShK-186 in rats and squirrel monkeys revealed a slow release from the injection site and blood levels above the channel blocking dose for 2 and 7 days, respectively.^[61] Studies on human peripheral blood T cells showed that a brief exposure to ShK-186 was sufficient to suppress cytokine responses.^[61] These findings suggest that ShK-186, despite its short circulating half-life, may have a prolonged therapeutic effect. In rats, the peptide is effective in treating disease in animal models of autoimmune diseases when administered once a day to once in 3 days.^[61] In humans, subcutaneous injections twice a week are sufficient to ameliorate disease in patients with plaque psoriasis.^[67]

Peptide delivery

The low molecular mass of ShK and its analogues, combined with their high isoelectric points, makes it unlikely that these peptides will be absorbed from the stomach or intestine following oral administration. Sub-lingual delivery is a possibility. A fluorescent ShK analogue was absorbed into the blood stream at pharmacological concentrations following sublingual administration with a mucoadhesive chitosan-based gel, with or without the penetration enhancer cetrimide.^[68] Delivery of the peptide as an aerosol through the lung, or across the skin, or as eye drops are also possibilities.^[69]^[70]^[71]

Modulation of T cell function

During T cell-activation, calcium enters lymphocytes through store-operated CRAC channels (calcium release activated channel) formed as a complex of Orai and Stim proteins.^[72]^[73] The rise in intracellular calcium initiates a signaling cascade culminating in cytokine production and proliferation.^[72]^[73] The K_v1.3 K⁺ channel and the calcium-activated K_Ca3.1 K⁺ channel in T cells promote calcium entry into the cytoplasm through CRAC by providing a counterbalancing cation efflux.^[74]^[72]^[73] Blockade of K_v1.3 depolarizes the membrane potential of T cells, suppresses calcium signaling and IL-2 production, but not IL2-receptor expression.^[75]^[76] ^[77]^[78]^[79] K_v1.3 blockers have no effect on activation pathways that are independent of a rise in intracellular calcium (e.g. anti-CD28, IL-2).^[75]^[76] Expression of the K_v1.3 and K_Ca3.1 channels varies during T cell activation and differentiation into memory T cells.^[74]^[72]^[73]^[80]^[81] When naïve T cells and central memory T cells (T_CM) are activated they upregulate K_Ca3.1 expression to ~500 per cell without significant change in K_v1.3 numbers.^[74]^[72]^[73]^[80]^[81] In contrast, when terminally differentiated effector memory subsets (T_EM, T_EMRA [T effector memory re-expressing CD45RA]) are activated, they upregulate K_v1.3 to 1500 per cell without changes in K_Ca3.1.^[74]^[72]^[73]^[80]^[81] The K_v1.3 channel number increases and the K_Ca3.1 channel number decreases as T cells are chronically activated.^[72]^[73]^[80]^[81]^[82] As a result of this differential expression, blockers of K_Ca3.1 channels preferentially suppress the function of naïve and T_CM cells, while ShK and its analogues that selectively inhibit K_v1.3 channels preferentially suppress the function of chronically-activated effector memory T cells (T_EM, T_EMRA).^[74]^[72]^[73]^[80]^[81]

Of special interest are the large number of ShK analogues developed at Amgen that suppressed interleukin-2 and interferon gamma production by T cells.^[83] This inhibitory effect of K_v1.3 blockers is partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulation.^[84] Chronically-activated CD28^null effector memory T cells are implicated in autoimmune diseases (e.g. lupus, Crohn’s disease, rheumatoid arthritis, multiple sclerosis).^[85]^[86]^[87]^[88]

Blockade of K_v1.3 channels in these chronically-activated T cells suppresses calcium signaling, cytokine production (interferon gamma, interleukin-2, interleukin 17), and cell proliferation.^[89]^[74]^[90]^[91]^[72]^[73]^[80]^[81] Effector memory T cells that are CD28⁺ are refractory to suppression by K_v1.3 blockers when they are co-stimulated by anti-CD3 and anti-CD28 antibodies, but are sensitive to suppression when stimulated by anti-CD3 antibodies alone.^[81] In vivo, ShK-186 paralyzes effector-memory T cells at the site of an inflammatory delayed type hypersensitivity response and prevents these T cells from activating in the inflamed tissue.^[92] In contrast, ShK-186 does not affect the homing and motility of naive and T_CM cells to and within lymph nodes, most likely because these cells express the K_Ca3.1 channel and are therefore protected from the effect of K_v1.3 blockade.^[92]

Effects on microglia

K_v1.3 plays an important role in microglial activation.^[93]^[94]^[95]^[96] ShK-223, an analogue of ShK-186, decreased lipopolysaccharide (LPS) induced focal adhesion formation by microglia, reversed LPS-induced inhibition of microglial migration, and inhibited LPS-induced upregulation of EH domain containing protein 1 (EHD1), a protein involved in microglia trafficking.^[97] Increased K_v1.3 expression was reported in microglia in Alzheimer plaques.^[98] K_v1.3 inhibitors may have use in the management of Alzheimer’s disease, as reported in a proof-of-concept study in which a small molecule K_v1.3 blocker (PAP-1) alleviated Alzheimer’s disease-like characteristics in a mouse model of AD.^[99]

Toxicity

Toxicity of ShK toxin in mice is quite low. The median paralytic dose is about 25 mg/kg bodyweight (which translates to 0.5 mg per 20 g mouse). In rats the therapeutic safety index was greater than 75-fold.

ShK-Dap22 is less toxic, even a dose of 1.0 mg dose did not cause hyperactivity, seizures or mortality. The median paralytic dose was 200 mg/kg body weight.^[100]

ShK-170 [a.k.a. ShK(L5)] does not cause significant toxicity in vitro. The peptide was not toxic to human and rat lymphoid cells incubated for 48 h with 100 nM of ShK-170 (>1200 times greater than the K_v1.3 half-blocking dose). The same high concentration of ShK-170 was negative in the Ames test on tester strain TA97A, suggesting that it is not a mutagen. ShK-170 had no effect on heart rate or heart rate variability parameters in either the time or the frequency domain in rats. It does not block the hERG (K_v11.1) channel that is associated with drug-associated cardiac arrhythmias. Repeated daily administration of the peptide by subcutaneous injection (10 µg/kg/day) for 2 weeks to rats does not cause any changes in blood counts, blood chemistry or in the proportion of thymocyte or lymphocyte subsets. Furthermore, the rats administered the peptide gain weight normally.

ShK-186 [a.k.a. SL5] is also safe. Repeated daily administration by subcutaneous injection of ShK-186 (100 µg/kg/day) for 4 weeks to rats does not cause any changes in blood counts, blood chemistry or histopathology.^[101] Furthermore, ShK-186 did not compromise the protective immune response to acute influenza viral infection or acute bacterial (Chlamydia) infection in rats at concentrations that were effective in ameliorating autoimmune diseases in rat models.^[102] Interestingly, rats repeatedly administered ShK-186 for a month by subcutaneous injection (500 µg/kg/day) developed low titer anti-ShK antibodies.^[103] The reason for the low immunogenicity of the peptide is not well understood. ShK-186 has completed GLP (Good Laboratory Practice) non-clinical safety studies in rodents and non-human primates. ShK-186 (aka Dalazatide) which was licensed to Kineta Bio is the subject of an open Investigational New Drug (IND) application in the United States of America, and has recently completed human phase 1A and 1b trials in healthy volunteers. A second human phase 1b was recently completed in 2015 in psoriasis patients. Dalazatide was shown to significantly ameliorate symptoms in 90% patients with active plaque psoriasis with a 60 mcg weekly dose.

Many groups are developing K_v1.3 blockers for the treatment of autoimmune diseases.^[104]

Use

Because ShK toxin is a specific inhibitor of K_v1.1, K_v1.3, K_v1.6, K_v3.2 and K_Ca3.1, it may serve as a useful pharmacological tool for studying these channels.^[105]^[106] The K_v1.3 specific ShK analogs, ShK-170, ShK-186 and ShK-192, have been demonstrated to be effective in rat models of autoimmune diseases, and these or related analogs might have use as therapeutics for human autoimmune diseases.

K_v1.3 is also considered a therapeutic target for the treatment of obesity,^[107]^[108] for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus,^[109] and for preventing bone resorption in periodontal disease.^[110] Furthermore, because pancreatic beta cells, which have K_v3.2 channels, are thought to play a role in glucose-dependent firing, ShK, as a K_v3.2 blocker, might be useful in the treatment of type-2 diabetes, although inhibition of the delayed-rectifier current has not yet been observed in human cells even when very high ShK concentrations were used.^[111]

References

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^ Castañeda, O; Sotolongo, V; Amor, AM; Stöcklin, R; Anderson, AJ; Harvey, AL; Engström, A; Wernstedt, C; Karlsson, E (1995). "Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus". Toxicon. 33 (5): 603-613. doi:10.1016/0041-0101(95)00013-C.
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^ Beeton, C; Pennington, MW; Wulff, H; Singh, S; Nugent, D; Crossley, G; Khaytin, I; Calabresi, PA; Chen, CY; Gutman, GA; Chandy, KG (2005). "Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases". Molecular Pharmacology. 67 (4): 1369-1381. doi:10.1124/mol.104.008193. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Beeton, C; Wulff, H; Standifer, NE; Azam, P; Mullen, KM; Pennington, MW; Kolski-Andreaco, A; Wei, E; Grino, A; Counts, DR; Wang, PH; LeeHealey, CJ; Andrews, BS; Sankaranarayanan, A; Homerick, D; Roeck, WW; Tehranzadeh, J; Stanhope, KL; Zimin, P; Havel, PJ; Griffey, S; Knaus, HG; Nepom, GT; Gutman, GA; Calabresi, PA; Chandy, KG (2006). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17414–17419. doi:10.1073/pnas.0605136103. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Tarcha, Eric J.; Olsen, Chelsea M.; Probst, Peter; Peckham, David; Muñoz-Elías, Ernesto J.; Kruger, James G.; Iadonato, Shawn P. (2017-07-19). "Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial". PLOS ONE. 12 (7): e0180762. doi:10.1371/journal.pone.0180762. ISSN 1932-6203. PMC 5516987. PMID 28723914.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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^ Pennington, Michael W.; Lanigan, Mark D.; Kalman, Katalin; Mahnir, Vladimir M.; Rauer, Heiko; McVaugh, Cheryl T.; Behm, David; Donaldson, Denise; Chandy, K. George (1999). "Role of Disulfide Bonds in the Structure and Potassium Channel Blocking Activity of ShK Toxin†". Biochemistry. 38 (44): 14549–14558. doi:10.1021/bi991282m. ISSN 0006-2960.
^ Lanigan, Mark D.; Tudor, Jane E.; Pennington, Michael W.; Norton, Raymond S. (2001). "A helical capping motif in ShK toxin and its role in helix stabilization". Biopolymers. 58 (4): 422–436. ISSN 0006-3525.
^ Baell, Jonathan B.; Harvey, Andrew J.; Norton, Raymond S. (2002). "Design and synthesis of type-III mimetics of ShK toxin". Journal of Computer-Aided Molecular Design. 16 (4): 245–262. doi:10.1023/a:1016310602813. ISSN 0920-654X.
^ Chang, Shih Chieh; Galea, Charles A.; Leung, Eleanor W.W.; Tajhya, Rajeev B.; Beeton, Christine; Pennington, Michael W.; Norton, Raymond S. (2012). "Expression and isotopic labelling of the potassium channel blocker ShK toxin as a thioredoxin fusion protein in bacteria". Toxicon. 60 (5): 840–850. doi:10.1016/j.toxicon.2012.05.017. ISSN 0041-0101.
^ Dang, Bobo; Kubota, Tomoya; Mandal, Kalyaneswar; Bezanilla, Francisco; Kent, Stephen B. H. (2013). "Native Chemical Ligation at Asx-Cys, Glx-Cys: Chemical Synthesis and High-Resolution X-ray Structure of ShK Toxin by Racemic Protein Crystallography". Journal of the American Chemical Society. 135 (32): 11911–11919. doi:10.1021/ja4046795. ISSN 0002-7863.
^ Lioudyno, Maria I.; Birch, Alexandra M.; Tanaka, Brian S.; Sokolov, Yuri; Goldin, Alan L.; Chandy, K. George; Hall, James E.; Alkire, Michael T. (2013). "Shaker-Related Potassium Channels in the Central Medial Nucleus of the Thalamus Are Important Molecular Targets for Arousal Suppression by Volatile General Anesthetics". Journal of Neuroscience. 33 (41): 16310–16322. doi:10.1523/jneurosci.0344-13.2013. PMC 3792466. PMID 24107962.{{cite journal}}: CS1 maint: PMC format (link)
^ Chhabra, Sandeep; Chang, Shih Chieh; Nguyen, Hai M.; Huq, Redwan; Tanner, Mark R.; Londono, Luz M.; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra (2014). "Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases". The FASEB Journal. 28 (9): 3952–3964. doi:10.1096/fj.14-251967. ISSN 0892-6638.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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^ Tudor, JE; Pallaghy, PK; Pennington, W; Norton, RS (1996). "Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone". Nature Structural & Molecular Biology. 3: 317–320. doi:10.1038/nsb0496-317. {{cite journal}}: Unknown parameter |month= ignored (help)
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[Tudor_1996-1] Cite error: The named reference Tudor_1996 was invoked but never defined (see the help page).

[2] Norton, Raymond; Pennington, Michael; Wulff, Heike (2004-12-01). "Potassium Channel Blockade by the Sea Anemone Toxin ShK for the Treatment of Multiple Sclerosis and Other Autoimmune Diseases". Current Medicinal Chemistry. 11 (23): 3041–3052. doi:10.2174/0929867043363947. ISSN 0929-8673.

[3] Castañeda, O; Sotolongo, V; Amor, AM; Stöcklin, R; Anderson, AJ; Harvey, AL; Engström, A; Wernstedt, C; Karlsson, E (1995). "Characterization of a potassium channel toxin from the Caribbean Sea anemone Stichodactyla helianthus". Toxicon. 33 (5): 603-613. doi:10.1016/0041-0101(95)00013-C.

[4] Pennington, M; Byrnes, ME; Zaydenberg, I; Khaytin, I; de Chastonay, J; Krafte, DS; Hill, R; Mahnir, VM; Volberg, WA; Gorczyca, W (1995). "Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone". International Journal of Peptide and Protein Research. 46 (5): 354-358. doi:10.1111/j.1399-3011.1995.tb01068.x. {{cite journal}}: Unknown parameter |month= ignored (help)

[solution_structure-5] Tudor, JE; Pallaghy, PK; Pennington, W; Norton, RS (1996). "Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone". Nature Structural & Molecular Biology. 3: 317–320. doi:10.1038/nsb0496-317. {{cite journal}}: Unknown parameter |month= ignored (help)

[Targeting_effector_memory-6] Beeton, C; Pennington, MW; Wulff, H; Singh, S; Nugent, D; Crossley, G; Khaytin, I; Calabresi, PA; Chen, CY; Gutman, GA; Chandy, KG (2005). "Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases". Molecular Pharmacology. 67 (4): 1369-1381. doi:10.1124/mol.104.008193. {{cite journal}}: Unknown parameter |month= ignored (help)

[Kv1.3-7] Beeton, C; Wulff, H; Standifer, NE; Azam, P; Mullen, KM; Pennington, MW; Kolski-Andreaco, A; Wei, E; Grino, A; Counts, DR; Wang, PH; LeeHealey, CJ; Andrews, BS; Sankaranarayanan, A; Homerick, D; Roeck, WW; Tehranzadeh, J; Stanhope, KL; Zimin, P; Havel, PJ; Griffey, S; Knaus, HG; Nepom, GT; Gutman, GA; Calabresi, PA; Chandy, KG (2006). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17414–17419. doi:10.1073/pnas.0605136103. {{cite journal}}: Unknown parameter |month= ignored (help)

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[19] Lioudyno, Maria I.; Birch, Alexandra M.; Tanaka, Brian S.; Sokolov, Yuri; Goldin, Alan L.; Chandy, K. George; Hall, James E.; Alkire, Michael T. (2013). "Shaker-Related Potassium Channels in the Central Medial Nucleus of the Thalamus Are Important Molecular Targets for Arousal Suppression by Volatile General Anesthetics". Journal of Neuroscience. 33 (41): 16310–16322. doi:10.1523/jneurosci.0344-13.2013. PMC 3792466. PMID 24107962.{{cite journal}}: CS1 maint: PMC format (link)

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[solution_structure2-22] Tudor, JE; Pallaghy, PK; Pennington, W; Norton, RS (1996). "Solution structure of ShK toxin, a novel potassium channel inhibitor from a sea anemone". Nature Structural & Molecular Biology. 3: 317–320. doi:10.1038/nsb0496-317. {{cite journal}}: Unknown parameter |month= ignored (help)

[:0-23] Kalman, K.; Pennington, M. W.; Lanigan, M. D.; Nguyen, A.; Rauer, H.; Mahnir, V.; Paschetto, K.; Kem, W. R.; Grissmer, S. (1998-12-04). "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". The Journal of Biological Chemistry. 273 (49): 32697–32707. ISSN 0021-9258. PMID 9830012.

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[:72-34] Chandy, K George; Norton, Raymond S (2017-06). "Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease". Current Opinion in Chemical Biology. 38: 97–107. doi:10.1016/j.cbpa.2017.02.015. ISSN 1367-5931. {{cite journal}}: Check date values in: |date= (help)

[:82-35] Gilquin, Bernard; Braud, Sandrine; Eriksson, Mats A. L.; Roux, Benoît; Bailey, Timothy D.; Priest, Birgit T.; Garcia, Maria L.; Ménez, André; Gasparini, Sylvaine (2005-07-22). "A variable residue in the pore of Kv1 channels is critical for the high affinity of blockers from sea anemones and scorpions". The Journal of Biological Chemistry. 280 (29): 27093–27102. doi:10.1074/jbc.M413626200. ISSN 0021-9258. PMID 15890656.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[:04-36] Kalman, K.; Pennington, M. W.; Lanigan, M. D.; Nguyen, A.; Rauer, H.; Mahnir, V.; Paschetto, K.; Kem, W. R.; Grissmer, S. (1998-12-04). "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". The Journal of Biological Chemistry. 273 (49): 32697–32707. ISSN 0021-9258. PMID 9830012.

[Targeting_effector_memory2-37] Beeton, C; Pennington, MW; Wulff, H; Singh, S; Nugent, D; Crossley, G; Khaytin, I; Calabresi, PA; Chen, CY; Gutman, GA; Chandy, KG (2005). "Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases". Molecular Pharmacology. 67 (4): 1369-1381. doi:10.1124/mol.104.008193. {{cite journal}}: Unknown parameter |month= ignored (help)

[:03-38] Kalman, K.; Pennington, M. W.; Lanigan, M. D.; Nguyen, A.; Rauer, H.; Mahnir, V.; Paschetto, K.; Kem, W. R.; Grissmer, S. (1998-12-04). "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". The Journal of Biological Chemistry. 273 (49): 32697–32707. ISSN 0021-9258. PMID 9830012.

[:63-39] Pennington, M. W.; Beeton, C.; Galea, C. A.; Smith, B. J.; Chi, V.; Monaghan, K. P.; Garcia, A.; Rangaraju, S.; Giuffrida, A. (2009-4). "Engineering a Stable and Selective Peptide Blocker of the Kv1.3 Channel in T Lymphocytes". Molecular Pharmacology. 75 (4): 762–773. doi:10.1124/mol.108.052704. ISSN 0026-895X. PMC 2684922. PMID 19122005. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[:163-40] Chang, Shih C.; Huq, Redwan; Chhabra, Sandeep; Beeton, Christine; Pennington, Michael W.; Smith, Brian J.; Norton, Raymond S. (2015-04-23). "N-terminally extended analogues of the K+ channel toxin from Stichodactyla helianthusas potent and selective blockers of the voltage-gated potassium channel Kv1.3". FEBS Journal. 282 (12): 2247–2259. doi:10.1111/febs.13294. ISSN 1742-464X. PMC 4472561. PMID 25864722. {{cite journal}}: no-break space character in |title= at position 75 (help)CS1 maint: PMC format (link)

[41] Pennington, M. W.; Mahnir, V. M.; Khaytin, I.; Zaydenberg, I.; Byrnes, M. E.; Kem, W. R. (January 1996). "An Essential Binding Surface for ShK Toxin Interaction with Rat Brain Potassium Channels†". Biochemistry. 35 (51): 16407–16411. doi:10.1021/bi962463g. ISSN 0006-2960.

[:2-42] Lanigan, Mark D.; Kalman, Katalin; Lefievre, Yann; Pennington, Michael W.; Chandy, K. George; Norton, Raymond S. (2002-10-08). "Mutating a critical lysine in ShK toxin alters its binding configuration in the pore-vestibule region of the voltage-gated potassium channel, Kv1.3". Biochemistry. 41 (40): 11963–11971. ISSN 0006-2960. PMID 12356296.

[:7-43] ^ ^a ^b ^c ^d ^e ^f Chandy, K George; Norton, Raymond S (2017-06). "Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease". Current Opinion in Chemical Biology. 38: 97–107. doi:10.1016/j.cbpa.2017.02.015. ISSN 1367-5931. {{cite journal}}: Check date values in: |date= (help)

[:1-44] Rauer, H.; Pennington, M.; Cahalan, M.; Chandy, K. G. (1999-07-30). "Structural conservation of the pores of calcium-activated and voltage-gated potassium channels determined by a sea anemone toxin". The Journal of Biological Chemistry. 274 (31): 21885–21892. ISSN 0021-9258. PMID 10419508.

[:8-45] Gilquin, Bernard; Braud, Sandrine; Eriksson, Mats A. L.; Roux, Benoît; Bailey, Timothy D.; Priest, Birgit T.; Garcia, Maria L.; Ménez, André; Gasparini, Sylvaine (2005-07-22). "A variable residue in the pore of Kv1 channels is critical for the high affinity of blockers from sea anemones and scorpions". The Journal of Biological Chemistry. 280 (29): 27093–27102. doi:10.1074/jbc.M413626200. ISSN 0021-9258. PMID 15890656.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[46] Stehling, Eliana G.; Sforça, Mauricio L.; Zanchin, Nilson I. T.; Oyama, Sérgio; Pignatelli, Angela; Belluzzi, Ottorino; Polverini, Eugenia; Corsini, Romina; Spisni, Alberto (2012-02-27). "Looking over Toxin–K+ Channel Interactions. Clues from the Structural and Functional Characterization of α-KTx Toxin Tc32, a Kv1.3 Channel Blocker". Biochemistry. 51 (9): 1885–1894. doi:10.1021/bi201713z. ISSN 0006-2960.

[:05-47] Kalman, K.; Pennington, M. W.; Lanigan, M. D.; Nguyen, A.; Rauer, H.; Mahnir, V.; Paschetto, K.; Kem, W. R.; Grissmer, S. (1998-12-04). "ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide". The Journal of Biological Chemistry. 273 (49): 32697–32707. ISSN 0021-9258. PMID 9830012.

[:22-48] Lanigan, Mark D.; Kalman, Katalin; Lefievre, Yann; Pennington, Michael W.; Chandy, K. George; Norton, Raymond S. (2002-10-08). "Mutating a critical lysine in ShK toxin alters its binding configuration in the pore-vestibule region of the voltage-gated potassium channel, Kv1.3". Biochemistry. 41 (40): 11963–11971. ISSN 0006-2960. PMID 12356296.

[:3-49] Middleton, Richard E.; Sanchez, Manuel; Linde, Ana-Rosa; Bugianesi, Randal M.; Dai, Ge; Felix, John P.; Koprak, Sam L.; Staruch, Mary Jo; Bruguera, Marc (2003-11-25). "Substitution of a single residue in Stichodactyla helianthus peptide, ShK-Dap22, reveals a novel pharmacological profile". Biochemistry. 42 (46): 13698–13707. doi:10.1021/bi035209e. ISSN 0006-2960. PMID 14622016.

[50] Aiyar, Jayashree; Rizzi, James P.; Gutman, George A.; Chandy, K. George (1996-12-06). "The Signature Sequence of Voltage-gated Potassium Channels Projects into the External Vestibule". Journal of Biological Chemistry. 271 (49): 31013–31016. doi:10.1074/jbc.271.49.31013. ISSN 0021-9258. PMID 8940091.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[:4-51] Beeton, Christine; Wulff, Heike; Singh, Satendra; Botsko, Steve; Crossley, George; Gutman, George A.; Cahalan, Michael D.; Pennington, Michael; Chandy, K. George (2003-03-14). "A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes". The Journal of Biological Chemistry. 278 (11): 9928–9937. doi:10.1074/jbc.M212868200. ISSN 0021-9258. PMID 12511563.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[:64-52] Pennington, M. W.; Beeton, C.; Galea, C. A.; Smith, B. J.; Chi, V.; Monaghan, K. P.; Garcia, A.; Rangaraju, S.; Giuffrida, A. (2009-4). "Engineering a Stable and Selective Peptide Blocker of the Kv1.3 Channel in T Lymphocytes". Molecular Pharmacology. 75 (4): 762–773. doi:10.1124/mol.108.052704. ISSN 0026-895X. PMC 2684922. PMID 19122005. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[:164-53] Chang, Shih C.; Huq, Redwan; Chhabra, Sandeep; Beeton, Christine; Pennington, Michael W.; Smith, Brian J.; Norton, Raymond S. (2015-04-23). "N-terminally extended analogues of the K+ channel toxin from Stichodactyla helianthusas potent and selective blockers of the voltage-gated potassium channel Kv1.3". FEBS Journal. 282 (12): 2247–2259. doi:10.1111/febs.13294. ISSN 1742-464X. PMC 4472561. PMID 25864722. {{cite journal}}: no-break space character in |title= at position 75 (help)CS1 maint: PMC format (link)

[:73-54] Chandy, K George; Norton, Raymond S (2017-06). "Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease". Current Opinion in Chemical Biology. 38: 97–107. doi:10.1016/j.cbpa.2017.02.015. ISSN 1367-5931. {{cite journal}}: Check date values in: |date= (help)

[Targeting_effector_memory3-55] Beeton, C; Pennington, MW; Wulff, H; Singh, S; Nugent, D; Crossley, G; Khaytin, I; Calabresi, PA; Chen, CY; Gutman, GA; Chandy, KG (2005). "Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases". Molecular Pharmacology. 67 (4): 1369-1381. doi:10.1124/mol.104.008193. {{cite journal}}: Unknown parameter |month= ignored (help)

[:13-56] Tarcha, Eric J.; Chi, Victor; Muñoz-Elías, Ernesto J.; Bailey, David; Londono, Luz M.; Upadhyay, Sanjeev K.; Norton, Kayla; Banks, Amy; Tjong, Indra (2012-09-01). "Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease". Journal of Pharmacology and Experimental Therapeutics. 342 (3): 642–653. doi:10.1124/jpet.112.191890. PMC 3422530. PMID 22637724.{{cite journal}}: CS1 maint: PMC format (link)

[:14-57] Chi, Victor; Pennington, Michael W.; Norton, Raymond S.; Tarcha, Eric J.; Londono, Luz M.; Sims-Fahey, Brian; Upadhyay, Sanjeev K.; Lakey, Jonathan T.; Iadonato, Shawn (2012-03). "Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases". Toxicon. 59 (4): 529–546. doi:10.1016/j.toxicon.2011.07.016. ISSN 0041-0101. PMC 3397671. PMID 21867724. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[:21-58] Rashid, M. Harunur; Heinzelmann, Germano; Huq, Redwan; Tajhya, Rajeev B.; Chang, Shih Chieh; Chhabra, Sandeep; Pennington, Michael W.; Beeton, Christine; Norton, Raymond S. (2013-11-07). "A Potent and Selective Peptide Blocker of the Kv1.3 Channel: Prediction from Free-Energy Simulations and Experimental Confirmation". PLOS ONE. 8 (11): e78712. doi:10.1371/journal.pone.0078712. ISSN 1932-6203. PMC 3820677. PMID 24244345.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[:27-59] Chhabra, Sandeep; Chang, Shih Chieh; Nguyen, Hai M.; Huq, Redwan; Tanner, Mark R.; Londono, Luz M.; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra (2014-09). "Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases". The FASEB Journal. 28 (9): 3952–3964. doi:10.1096/fj.14-251967. ISSN 0892-6638. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)

[:28-60] McNeilly, Tom N.; Frew, David; Burgess, Stewart T. G.; Wright, Harry; Bartley, David J.; Bartley, Yvonne; Nisbet, Alasdair J. (2017-08-03). "Niche-specific gene expression in a parasitic nematode; increased expression of immunomodulators in Teladorsagia circumcincta larvae derived from host mucosa". Scientific Reports. 7 (1). doi:10.1038/s41598-017-07092-0. ISSN 2045-2322.

[:132-61] Tarcha, Eric J.; Chi, Victor; Muñoz-Elías, Ernesto J.; Bailey, David; Londono, Luz M.; Upadhyay, Sanjeev K.; Norton, Kayla; Banks, Amy; Tjong, Indra (2012-09-01). "Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease". Journal of Pharmacology and Experimental Therapeutics. 342 (3): 642–653. doi:10.1124/jpet.112.191890. PMC 3422530. PMID 22637724.{{cite journal}}: CS1 maint: PMC format (link)

[:153-62] Murray, Justin K.; Qian, Yi-Xin; Liu, Benxian; Elliott, Robin; Aral, Jennifer; Park, Cynthia; Zhang, Xuxia; Stenkilsson, Michael; Salyers, Kevin (2015-08-31). "Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3". Journal of Medicinal Chemistry. 58 (17): 6784–6802. doi:10.1021/acs.jmedchem.5b00495. ISSN 0022-2623.

[:74-63] Chandy, K George; Norton, Raymond S (2017-06). "Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease". Current Opinion in Chemical Biology. 38: 97–107. doi:10.1016/j.cbpa.2017.02.015. ISSN 1367-5931. {{cite journal}}: Check date values in: |date= (help)

[64] Edwards, Wilson; Fung-Leung, Wai-Ping; Huang, Chichi; Chi, Ellen; Wu, Nancy; Liu, Yi; Maher, Michael P.; Bonesteel, Rachelle; Connor, Judith (2014-08-15). "Targeting the Ion Channel Kv1.3 with Scorpion Venom Peptides Engineered for Potency, Selectivity, and Half-life". Journal of Biological Chemistry. 289 (33): 22704–22714. doi:10.1074/jbc.M114.568642. ISSN 0021-9258. PMC 4132777. PMID 24939846.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[65] Wang, Rongsheng E.; Wang, Ying; Zhang, Yuhan; Gabrelow, Chase; Zhang, Yong; Chi, Victor; Fu, Qiangwei; Luo, Xiaozhou; Wang, Danling (2016-10-11). "Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant". Proceedings of the National Academy of Sciences. 113 (41): 11501–11506. doi:10.1073/pnas.1612803113. PMC 5068325. PMID 27663736.{{cite journal}}: CS1 maint: PMC format (link)

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[:202-67] Tarcha, Eric J.; Olsen, Chelsea M.; Probst, Peter; Peckham, David; Muñoz-Elías, Ernesto J.; Kruger, James G.; Iadonato, Shawn P. (2017-07-19). "Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial". PLOS ONE. 12 (7): e0180762. doi:10.1371/journal.pone.0180762. ISSN 1932-6203. PMC 5516987. PMID 28723914.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[68] Jin, Liang; Boyd, Ben J.; White, Paul J.; Pennington, Michael W.; Norton, Raymond S.; Nicolazzo, Joseph A. (2015-02). "Buccal mucosal delivery of a potent peptide leads to therapeutically-relevant plasma concentrations for the treatment of autoimmune diseases". Journal of Controlled Release. 199: 37–44. doi:10.1016/j.jconrel.2014.12.001. ISSN 0168-3659. {{cite journal}}: Check date values in: |date= (help)

[69] Jin, Liang; Zhou, Qi (Tony); Chan, Hak-Kim; Larson, Ian C.; Pennington, Michael W.; Morales, Rodrigo A.V.; Boyd, Ben J.; Norton, Raymond S.; Nicolazzo, Joseph A. (2016-02). "Pulmonary Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] for the Treatment of Autoimmune Diseases". Journal of Pharmaceutical Sciences. 105 (2): 650–656. doi:10.1016/j.xphs.2015.10.025. ISSN 0022-3549. {{cite journal}}: Check date values in: |date= (help)

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[Kv1.32-89] Beeton, C; Wulff, H; Standifer, NE; Azam, P; Mullen, KM; Pennington, MW; Kolski-Andreaco, A; Wei, E; Grino, A; Counts, DR; Wang, PH; LeeHealey, CJ; Andrews, BS; Sankaranarayanan, A; Homerick, D; Roeck, WW; Tehranzadeh, J; Stanhope, KL; Zimin, P; Havel, PJ; Griffey, S; Knaus, HG; Nepom, GT; Gutman, GA; Calabresi, PA; Chandy, KG (2006). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17414–17419. doi:10.1073/pnas.0605136103. {{cite journal}}: Unknown parameter |month= ignored (help)

[:142-90] Chi, Victor; Pennington, Michael W.; Norton, Raymond S.; Tarcha, Eric J.; Londono, Luz M.; Sims-Fahey, Brian; Upadhyay, Sanjeev K.; Lakey, Jonathan T.; Iadonato, Shawn (2012-03). "Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases". Toxicon. 59 (4): 529–546. doi:10.1016/j.toxicon.2011.07.016. ISSN 0041-0101. PMC 3397671. PMID 21867724. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

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@@ Line 89: / Line 89: @@
 == Modulation of T cell function ==
-<p>During T cell-activation, calcium enters lymphocytes through store-operated CRAC channels (calcium release activated channel) formed as a complex of Orai and Stim proteins.<ref name=":222">{{Cite journal|last=Cahalan|first=Michael D.|last2=Chandy|first2=K. George|date=2009-09|title=The functional network of ion channels in T lymphocytes|url=http://doi.wiley.com/10.1111/j.1600-065X.2009.00816.x|journal=Immunological Reviews|language=en|volume=231|issue=1|pages=59–87|doi=10.1111/j.1600-065x.2009.00816.x|issn=0105-2896|pmc=PMC3133616|pmid=19754890}}</ref><ref name=":23">{{Cite journal|last=Feske|first=Stefan|last2=Wulff|first2=Heike|last3=Skolnik|first3=Edward Y.|date=2015-03-21|title=Ion Channels in Innate and Adaptive Immunity|url=http://www.annualreviews.org/doi/10.1146/annurev-immunol-032414-112212|journal=Annual Review of Immunology|language=en|volume=33|issue=1|pages=291–353|doi=10.1146/annurev-immunol-032414-112212|issn=0732-0582|pmc=PMC4822408|pmid=25861976}}</ref> The rise in intracellular calcium initiates a signaling cascade culminating in cytokine production and proliferation.<ref name=":222" /><ref name=":23" /> The K<sub>v</sub>1.3 K<sup>+</sup> channel and the calcium-activated K<sub href="Digital object identifier">Ca</sub>3.1 K<sup>+</sup> channel in T cells promote calcium entry into the cytoplasm through CRAC by providing a counterbalancing cation efflux.<ref name=":75">{{Cite journal|last=Chandy|first=K George|last2=Norton|first2=Raymond S|date=2017-06|title=Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease|url=http://linkinghub.elsevier.com/retrieve/pii/S1367593116302058|journal=Current Opinion in Chemical Biology|volume=38|pages=97–107|doi=10.1016/j.cbpa.2017.02.015|issn=1367-5931}}</ref><ref name=":222" /><ref name=":23" /> Blockade of K<sub href="International Standard Serial Number">v</sub>1.3 depolarizes the membrane potential of T cells, suppresses calcium signaling and IL-2 production, but not IL2-receptor expression.<ref name=":29">{{Cite journal|last=Lin|first=C. S.|last2=Boltz|first2=R. C.|last3=Blake|first3=J. T.|last4=Nguyen|first4=M.|last5=Talento|first5=A.|last6=Fischer|first6=P. A.|last7=Springer|first7=M. S.|last8=Sigal|first8=N. H.|last9=Slaughter|first9=R. S.|date=1993-03-01|title=Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation.|url=http://jem.rupress.org/content/177/3/637|journal=Journal of Experimental Medicine|language=en|volume=177|issue=3|pages=637–645|doi=10.1084/jem.177.3.637|issn=0022-1007|pmid=7679705}}</ref><ref name=":30">{{Cite journal|last=Chandy|first=K. G.|last2=DeCoursey|first2=T. E.|last3=Cahalan|first3=M. D.|last4=McLaughlin|first4=C.|last5=Gupta|first5=S.|date=1984-08-01|title=Voltage-gated potassium channels are required for human T lymphocyte activation.|url=http://jem.rupress.org/content/160/2/369|journal=Journal of Experimental Medicine|language=en|volume=160|issue=2|pages=369–385|doi=10.1084/jem.160.2.369|issn=0022-1007|pmid=6088661}}</ref> <ref>{{Cite journal|last=Leonard|first=R. J.|last2=Garcia|first2=M. L.|last3=Slaughter|first3=R. S.|last4=Reuben|first4=J. P.|date=1992-11-01|title=Selective blockers of voltage-gated K  channels depolarize human T lymphocytes: mechanism of the antiproliferative effect of charybdotoxin|url=http://www.pnas.org/cgi/doi/10.1073/pnas.89.21.10094|journal=Proceedings of the National Academy of Sciences|volume=89|issue=21|pages=10094–10098|doi=10.1073/pnas.89.21.10094}}</ref><ref>{{Cite journal|last=Defarias|first=F. P.|last2=Stevens|first2=S. P.|last3=Leonard|first3=R. J.|date=1995|title=Stable expression of human Kv1.3 potassium channels resets the resting membrane potential of cultured mammalian cells|url=https://www.ncbi.nlm.nih.gov/pubmed/8834000|journal=Receptors & Channels|volume=3|issue=4|pages=273–281|issn=1060-6823|pmid=8834000}}</ref><ref>{{Cite journal|last=Verheugen|first=J. A.|last2=Vijverberg|first2=H. P.|last3=Oortgiesen|first3=M.|last4=Cahalan|first4=M. D.|date=1995-06-01|title=Voltage-gated and Ca(2+)-activated K+ channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium.|url=http://jgp.rupress.org/content/105/6/765|journal=The Journal of General Physiology|language=en|volume=105|issue=6|pages=765–794|doi=10.1085/jgp.105.6.765|issn=0022-1295|pmid=7561743}}</ref> K<sub>v</sub>1.3 blockers have no effect on activation pathways that are independent of a rise in intracellular calcium (e.g. anti-CD28, IL-2).<ref name=":29" /><ref name=":30" /> Expression of the K<sub>v</sub>1.3 and K<sub>Ca</sub>3.1 channels varies during T cell activation and differentiation into memory T cells.<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24">{{Cite journal|last=Wulff|first=Heike|last2=Calabresi|first2=Peter A.|last3=Allie|first3=Rameeza|last4=Yun|first4=Sung|last5=Pennington|first5=Michael|last6=Beeton|first6=Christine|last7=Chandy|first7=K. George|date=2003-06-01|title=The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS|url=http://www.jci.org/articles/view/16921|journal=Journal of Clinical Investigation|language=en|volume=111|issue=11|pages=1703–1713|doi=10.1172/jci16921|issn=0021-9738|pmc=PMC156104|pmid=12782673}}</ref><ref name=":25">{{Cite journal|last=Hu|first=Lina|last2=Pennington|first2=Michael|last3=Jiang|first3=Qiong|last4=Whartenby|first4=Katharine A.|last5=Calabresi|first5=Peter A.|date=2007-10-01|title=Characterization of the Functional Properties of the Voltage-Gated Potassium Channel Kv1.3 in Human CD4+ T Lymphocytes|url=http://www.jimmunol.org/content/179/7/4563|journal=The Journal of Immunology|language=en|volume=179|issue=7|pages=4563–4570|doi=10.4049/jimmunol.179.7.4563|issn=0022-1767|pmid=17878353}}</ref> When naïve T cells and central memory T cells (T<sub>CM</sub>) are activated they upregulate K<sub>Ca</sub>3.1 expression to ~500 per cell without significant change in K<sub>v</sub>1.3 numbers.<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /> In contrast, when terminally differentiated effector memory subsets (T<sub>EM</sub>, T<sub>EMRA</sub> [T effector memory re-expressing CD45RA]) are activated, they upregulate K<sub>v</sub>1.3 to 1500 per cell without changes in K<sub href="Digital object identifier">Ca</sub>3.1.<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /> The K<sub>v</sub>1.3 channel number increases and the K<sub>Ca</sub>3.1 channel number decreases as T cells are chronically activated.<ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /><ref name=":31">{{Cite journal|last=Chiang|first=Eugene Y.|last2=Li|first2=Tianbo|last3=Jeet|first3=Surinder|last4=Peng|first4=Ivan|last5=Zhang|first5=Juan|last6=Lee|first6=Wyne P.|last7=DeVoss|first7=Jason|last8=Caplazi|first8=Patrick|last9=Chen|first9=Jun|date=2017-03-01|title=Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions|url=http://dx.doi.org/10.1038/ncomms14644|journal=Nature Communications|volume=8|pages=14644|doi=10.1038/ncomms14644|issn=2041-1723}}</ref> As a result of this differential expression, blockers of K<sub>Ca</sub>3.1 channels preferentially suppress the function of naïve and T<sub>CM</sub> cells, while ShK and its analogues that selectively inhibit K<sub>v</sub>1.3 channels preferentially suppress the function of chronically-activated effector memory T cells (T<sub>EM</sub>, T<sub>EMRA</sub>).<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /></p>Of special interest are the large number of ShK analogues developed at Amgen that suppressed interleukin-2 and interferon gamma production by T cells.<ref name=":152">{{Cite journal|last=Murray|first=Justin K.|last2=Qian|first2=Yi-Xin|last3=Liu|first3=Benxian|last4=Elliott|first4=Robin|last5=Aral|first5=Jennifer|last6=Park|first6=Cynthia|last7=Zhang|first7=Xuxia|last8=Stenkilsson|first8=Michael|last9=Salyers|first9=Kevin|date=2015-08-31|title=Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3|url=http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00495|journal=Journal of Medicinal Chemistry|language=EN|volume=58|issue=17|pages=6784–6802|doi=10.1021/acs.jmedchem.5b00495|issn=0022-2623}}</ref> This inhibitory effect of K<sub>v</sub>1.3 blockers is partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulation.<ref>{{Cite journal|last=Fung-Leung|first=Wai-Ping|last2=Edwards|first2=Wilson|last3=Liu|first3=Yi|last4=Ngo|first4=Karen|last5=Angsana|first5=Julianty|last6=Castro|first6=Glenda|last7=Wu|first7=Nancy|last8=Liu|first8=Xuejun|last9=Swanson|first9=Ronald V.|date=2017-01-20|title=T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers|url=http://dx.doi.org/10.1371/journal.pone.0170102|journal=PLOS ONE|volume=12|issue=1|pages=e0170102|doi=10.1371/journal.pone.0170102|issn=1932-6203}}</ref> Chronically-activated CD28<sup>null</sup> effector memory T cells are implicated in autoimmune diseases (e.g. lupus, Crohn’s disease, rheumatoid arthritis, multiple sclerosis).<ref>{{Cite journal|last=Namekawa|first=Takashi|last2=Snyder|first2=Melissa R.|last3=Yen|first3=Jeng-Hsien|last4=Goehring|first4=Brenda E.|last5=Leibson|first5=Paul J.|last6=Weyand|first6=Cornelia M.|last7=Goronzy|first7=Jörg J.|date=2000-07-15|title=Killer Cell Activating Receptors Function as Costimulatory Molecules on CD4+CD28null T Cells Clonally Expanded in Rheumatoid Arthritis|url=http://www.jimmunol.org/content/165/2/1138|journal=The Journal of Immunology|language=en|volume=165|issue=2|pages=1138–1145|doi=10.4049/jimmunol.165.2.1138|issn=0022-1767|pmid=10878393}}</ref><ref>{{Cite journal|last=Markovic-Plese|first=Silva|last2=Cortese|first2=Irene|last3=Wandinger|first3=Klaus-Peter|last4=McFarland|first4=Henry F.|last5=Martin|first5=Roland|date=2001-10-15|title=CD4+CD28– costimulation-independent T cells in multiple sclerosis|url=https://doi.org/10.1172/JCI200112516|journal=Journal of Clinical Investigation|language=en|volume=108|issue=8|pages=1185–1194|doi=10.1172/jci12516|issn=0021-9738|pmc=PMC209525|pmid=11602626}}</ref><ref>{{Cite journal|last=Tena|first=Jaime García De|last2=Manzano|first2=Luis|last3=Leal|first3=Juan Carlos|last4=Antonio|first4=Esther San|last5=Sualdea|first5=Verónica|last6=Álvarez-Mon|first6=Melchor|date=2004-03-01|title=Active Crohn's Disease Patients Show a Distinctive Expansion of Circulating Memory CD4+CD45RO+CD28null T Cells|url=https://link.springer.com/article/10.1023/B:JOCI.0000019784.20191.7f|journal=Journal of Clinical Immunology|language=en|volume=24|issue=2|pages=185–196|doi=10.1023/B:JOCI.0000019784.20191.7f|issn=0271-9142}}</ref><ref>{{Cite journal|last=Tena|first=Jaime García De|last2=Manzano|first2=Luis|last3=Leal|first3=Juan Carlos|last4=Antonio|first4=Esther San|last5=Sualdea|first5=Verónica|last6=Álvarez-Mon|first6=Melchor|date=2004-03-01|title=Active Crohn's Disease Patients Show a Distinctive Expansion of Circulating Memory CD4+CD45RO+CD28null T Cells|url=https://link.springer.com/article/10.1023/B:JOCI.0000019784.20191.7f|journal=Journal of Clinical Immunology|language=en|volume=24|issue=2|pages=185–196|doi=10.1023/B:JOCI.0000019784.20191.7f|issn=0271-9142}}</ref><p>Blockade of K<sub>v</sub>1.3 channels in these chronically-activated T cells suppresses calcium signaling, cytokine production (interferon gamma, interleukin-2, interleukin 17), and cell proliferation.<ref name="Kv1.32">{{cite journal|last1=Beeton|first1=C|last2=Wulff|first2=H|last3=Standifer|first3=NE|last4=Azam|first4=P|last5=Mullen|first5=KM|last6=Pennington|first6=MW|last7=Kolski-Andreaco|first7=A|last8=Wei|first8=E|last9=Grino|first9=A|year=2006|title=Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859943/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=103|issue=46|page=17414–17419|doi=10.1073/pnas.0605136103|last10=Counts|first10=DR|last11=Wang|first11=PH|last12=LeeHealey|first12=CJ|last13=Andrews|first13=BS|last14=Sankaranarayanan|first14=A|last15=Homerick|first15=D|last16=Roeck|first16=WW|last17=Tehranzadeh|first17=J|last18=Stanhope|first18=KL|last19=Zimin|first19=P|last20=Havel|first20=PJ|last21=Griffey|first21=S|last22=Knaus|first22=HG|last23=Nepom|first23=GT|last24=Gutman|first24=GA|last25=Calabresi|first25=PA|last26=Chandy|first26=KG|month=November 14,}}</ref><ref name=":75" /><ref name=":142">{{Cite journal|last=Chi|first=Victor|last2=Pennington|first2=Michael W.|last3=Norton|first3=Raymond S.|last4=Tarcha|first4=Eric J.|last5=Londono|first5=Luz M.|last6=Sims-Fahey|first6=Brian|last7=Upadhyay|first7=Sanjeev K.|last8=Lakey|first8=Jonathan T.|last9=Iadonato|first9=Shawn|date=2012-03|title=Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases|url=http://linkinghub.elsevier.com/retrieve/pii/S0041010111002479|journal=Toxicon|volume=59|issue=4|pages=529–546|doi=10.1016/j.toxicon.2011.07.016|issn=0041-0101|pmc=PMC3397671|pmid=21867724}}</ref><ref name=":212">{{Cite journal|last=Rashid|first=M. Harunur|last2=Heinzelmann|first2=Germano|last3=Huq|first3=Redwan|last4=Tajhya|first4=Rajeev B.|last5=Chang|first5=Shih Chieh|last6=Chhabra|first6=Sandeep|last7=Pennington|first7=Michael W.|last8=Beeton|first8=Christine|last9=Norton|first9=Raymond S.|date=2013-11-07|title=A Potent and Selective Peptide Blocker of the Kv1.3 Channel: Prediction from Free-Energy Simulations and Experimental Confirmation|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078712|journal=PLOS ONE|language=en|volume=8|issue=11|pages=e78712|doi=10.1371/journal.pone.0078712|issn=1932-6203|pmc=PMC3820677|pmid=24244345}}</ref><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /> Effector memory T cells that are CD28<sup>+</sup> are refractory to suppression by K<sub>v</sub>1.3 blockers when they are co-stimulated by anti-CD3 and anti-CD28 antibodies, but are sensitive to suppression when stimulated by anti-CD3 antibodies alone.<ref name=":25" /> <i>In vivo</i>, ShK-186 paralyzes effector-memory T cells at the site of an inflammatory delayed type hypersensitivity response and prevents these T cells from activating in the inflamed tissue.<ref name=":5">{{Cite journal|last=Matheu|first=Melanie P.|last2=Beeton|first2=Christine|last3=Garcia|first3=Adriana|last4=Chi|first4=Victor|last5=Rangaraju|first5=Srikant|last6=Safrina|first6=Olga|last7=Monaghan|first7=Kevin|last8=Uemura|first8=Marc I.|last9=Li|first9=Dan|date=2008-10-17|title=Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732399/|journal=Immunity|volume=29|issue=4|pages=602–614|doi=10.1016/j.immuni.2008.07.015|issn=1074-7613|pmc=PMC2732399|pmid=18835197}}</ref> In contrast, ShK-186 does not affect the homing and motility of naive and T<sub>CM</sub> cells to and within lymph nodes, most likely because these cells express the K<sub href="Help:CS1 errors#parameter_ignored">Ca</sub>3.1 channel and are therefore protected from the effect of K<sub href="Category:Pages with citations using unsupported parameters">v</sub>1.3 blockade.<ref name=":5" /></p>
+<p>During T cell-activation, calcium enters lymphocytes through store-operated CRAC channels (calcium release activated channel) formed as a complex of Orai and Stim proteins.<ref name=":222">{{Cite journal|last=Cahalan|first=Michael D.|last2=Chandy|first2=K. George|date=2009-09|title=The functional network of ion channels in T lymphocytes|url=http://doi.wiley.com/10.1111/j.1600-065X.2009.00816.x|journal=Immunological Reviews|language=en|volume=231|issue=1|pages=59–87|doi=10.1111/j.1600-065x.2009.00816.x|issn=0105-2896|pmc=PMC3133616|pmid=19754890}}</ref><ref name=":23">{{Cite journal|last=Feske|first=Stefan|last2=Wulff|first2=Heike|last3=Skolnik|first3=Edward Y.|date=2015-03-21|title=Ion Channels in Innate and Adaptive Immunity|url=http://www.annualreviews.org/doi/10.1146/annurev-immunol-032414-112212|journal=Annual Review of Immunology|language=en|volume=33|issue=1|pages=291–353|doi=10.1146/annurev-immunol-032414-112212|issn=0732-0582|pmc=PMC4822408|pmid=25861976}}</ref> The rise in intracellular calcium initiates a signaling cascade culminating in cytokine production and proliferation.<ref name=":222" /><ref name=":23" /> The K<sub>v</sub>1.3 K<sup>+</sup> channel and the calcium-activated K<sub href="Digital object identifier">Ca</sub>3.1 K<sup>+</sup> channel in T cells promote calcium entry into the cytoplasm through CRAC by providing a counterbalancing cation efflux.<ref name=":75">{{Cite journal|last=Chandy|first=K George|last2=Norton|first2=Raymond S|date=2017-06|title=Peptide blockers of K v 1.3 channels in T cells as therapeutics for autoimmune disease|url=http://linkinghub.elsevier.com/retrieve/pii/S1367593116302058|journal=Current Opinion in Chemical Biology|volume=38|pages=97–107|doi=10.1016/j.cbpa.2017.02.015|issn=1367-5931}}</ref><ref name=":222" /><ref name=":23" /> Blockade of K<sub href="International Standard Serial Number">v</sub>1.3 depolarizes the membrane potential of T cells, suppresses calcium signaling and IL-2 production, but not IL2-receptor expression.<ref name=":29">{{Cite journal|last=Lin|first=C. S.|last2=Boltz|first2=R. C.|last3=Blake|first3=J. T.|last4=Nguyen|first4=M.|last5=Talento|first5=A.|last6=Fischer|first6=P. A.|last7=Springer|first7=M. S.|last8=Sigal|first8=N. H.|last9=Slaughter|first9=R. S.|date=1993-03-01|title=Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation.|url=http://jem.rupress.org/content/177/3/637|journal=Journal of Experimental Medicine|language=en|volume=177|issue=3|pages=637–645|doi=10.1084/jem.177.3.637|issn=0022-1007|pmid=7679705}}</ref><ref name=":30">{{Cite journal|last=Chandy|first=K. G.|last2=DeCoursey|first2=T. E.|last3=Cahalan|first3=M. D.|last4=McLaughlin|first4=C.|last5=Gupta|first5=S.|date=1984-08-01|title=Voltage-gated potassium channels are required for human T lymphocyte activation.|url=http://jem.rupress.org/content/160/2/369|journal=Journal of Experimental Medicine|language=en|volume=160|issue=2|pages=369–385|doi=10.1084/jem.160.2.369|issn=0022-1007|pmid=6088661}}</ref> <ref>{{Cite journal|last=Leonard|first=R. J.|last2=Garcia|first2=M. L.|last3=Slaughter|first3=R. S.|last4=Reuben|first4=J. P.|date=1992-11-01|title=Selective blockers of voltage-gated K  channels depolarize human T lymphocytes: mechanism of the antiproliferative effect of charybdotoxin|url=http://www.pnas.org/cgi/doi/10.1073/pnas.89.21.10094|journal=Proceedings of the National Academy of Sciences|volume=89|issue=21|pages=10094–10098|doi=10.1073/pnas.89.21.10094}}</ref><ref>{{Cite journal|last=Defarias|first=F. P.|last2=Stevens|first2=S. P.|last3=Leonard|first3=R. J.|date=1995|title=Stable expression of human Kv1.3 potassium channels resets the resting membrane potential of cultured mammalian cells|url=https://www.ncbi.nlm.nih.gov/pubmed/8834000|journal=Receptors & Channels|volume=3|issue=4|pages=273–281|issn=1060-6823|pmid=8834000}}</ref><ref>{{Cite journal|last=Verheugen|first=J. A.|last2=Vijverberg|first2=H. P.|last3=Oortgiesen|first3=M.|last4=Cahalan|first4=M. D.|date=1995-06-01|title=Voltage-gated and Ca(2+)-activated K+ channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium.|url=http://jgp.rupress.org/content/105/6/765|journal=The Journal of General Physiology|language=en|volume=105|issue=6|pages=765–794|doi=10.1085/jgp.105.6.765|issn=0022-1295|pmid=7561743}}</ref> K<sub>v</sub>1.3 blockers have no effect on activation pathways that are independent of a rise in intracellular calcium (e.g. anti-CD28, IL-2).<ref name=":29" /><ref name=":30" /> Expression of the K<sub>v</sub>1.3 and K<sub>Ca</sub>3.1 channels varies during T cell activation and differentiation into memory T cells.<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24">{{Cite journal|last=Wulff|first=Heike|last2=Calabresi|first2=Peter A.|last3=Allie|first3=Rameeza|last4=Yun|first4=Sung|last5=Pennington|first5=Michael|last6=Beeton|first6=Christine|last7=Chandy|first7=K. George|date=2003-06-01|title=The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS|url=http://www.jci.org/articles/view/16921|journal=Journal of Clinical Investigation|language=en|volume=111|issue=11|pages=1703–1713|doi=10.1172/jci16921|issn=0021-9738|pmc=PMC156104|pmid=12782673}}</ref><ref name=":25">{{Cite journal|last=Hu|first=Lina|last2=Pennington|first2=Michael|last3=Jiang|first3=Qiong|last4=Whartenby|first4=Katharine A.|last5=Calabresi|first5=Peter A.|date=2007-10-01|title=Characterization of the Functional Properties of the Voltage-Gated Potassium Channel Kv1.3 in Human CD4+ T Lymphocytes|url=http://www.jimmunol.org/content/179/7/4563|journal=The Journal of Immunology|language=en|volume=179|issue=7|pages=4563–4570|doi=10.4049/jimmunol.179.7.4563|issn=0022-1767|pmid=17878353}}</ref> When naïve T cells and central memory T cells (T<sub>CM</sub>) are activated they upregulate K<sub>Ca</sub>3.1 expression to ~500 per cell without significant change in K<sub>v</sub>1.3 numbers.<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /> In contrast, when terminally differentiated effector memory subsets (T<sub>EM</sub>, T<sub>EMRA</sub> [T effector memory re-expressing CD45RA]) are activated, they upregulate K<sub>v</sub>1.3 to 1500 per cell without changes in K<sub href="Digital object identifier">Ca</sub>3.1.<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /> The K<sub>v</sub>1.3 channel number increases and the K<sub>Ca</sub>3.1 channel number decreases as T cells are chronically activated.<ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /><ref name=":31">{{Cite journal|last=Chiang|first=Eugene Y.|last2=Li|first2=Tianbo|last3=Jeet|first3=Surinder|last4=Peng|first4=Ivan|last5=Zhang|first5=Juan|last6=Lee|first6=Wyne P.|last7=DeVoss|first7=Jason|last8=Caplazi|first8=Patrick|last9=Chen|first9=Jun|date=2017-03-01|title=Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions|url=http://dx.doi.org/10.1038/ncomms14644|journal=Nature Communications|volume=8|pages=14644|doi=10.1038/ncomms14644|issn=2041-1723}}</ref> As a result of this differential expression, blockers of K<sub>Ca</sub>3.1 channels preferentially suppress the function of naïve and T<sub>CM</sub> cells, while ShK and its analogues that selectively inhibit K<sub>v</sub>1.3 channels preferentially suppress the function of chronically-activated effector memory T cells (T<sub>EM</sub>, T<sub>EMRA</sub>).<ref name=":75" /><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /></p>Of special interest are the large number of ShK analogues developed at Amgen that suppressed interleukin-2 and interferon gamma production by T cells.<ref name=":152">{{Cite journal|last=Murray|first=Justin K.|last2=Qian|first2=Yi-Xin|last3=Liu|first3=Benxian|last4=Elliott|first4=Robin|last5=Aral|first5=Jennifer|last6=Park|first6=Cynthia|last7=Zhang|first7=Xuxia|last8=Stenkilsson|first8=Michael|last9=Salyers|first9=Kevin|date=2015-08-31|title=Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3|url=http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00495|journal=Journal of Medicinal Chemistry|language=EN|volume=58|issue=17|pages=6784–6802|doi=10.1021/acs.jmedchem.5b00495|issn=0022-2623}}</ref> This inhibitory effect of K<sub>v</sub>1.3 blockers is partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulation.<ref>{{Cite journal|last=Fung-Leung|first=Wai-Ping|last2=Edwards|first2=Wilson|last3=Liu|first3=Yi|last4=Ngo|first4=Karen|last5=Angsana|first5=Julianty|last6=Castro|first6=Glenda|last7=Wu|first7=Nancy|last8=Liu|first8=Xuejun|last9=Swanson|first9=Ronald V.|date=2017-01-20|title=T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers|url=http://dx.doi.org/10.1371/journal.pone.0170102|journal=PLOS ONE|volume=12|issue=1|pages=e0170102|doi=10.1371/journal.pone.0170102|issn=1932-6203}}</ref> Chronically-activated CD28<sup>null</sup> effector memory T cells are implicated in autoimmune diseases (e.g. lupus, Crohn’s disease, rheumatoid arthritis, multiple sclerosis).<ref>{{Cite journal|last=Namekawa|first=Takashi|last2=Snyder|first2=Melissa R.|last3=Yen|first3=Jeng-Hsien|last4=Goehring|first4=Brenda E.|last5=Leibson|first5=Paul J.|last6=Weyand|first6=Cornelia M.|last7=Goronzy|first7=Jörg J.|date=2000-07-15|title=Killer Cell Activating Receptors Function as Costimulatory Molecules on CD4+CD28null T Cells Clonally Expanded in Rheumatoid Arthritis|url=http://www.jimmunol.org/content/165/2/1138|journal=The Journal of Immunology|language=en|volume=165|issue=2|pages=1138–1145|doi=10.4049/jimmunol.165.2.1138|issn=0022-1767|pmid=10878393}}</ref><ref>{{Cite journal|last=Markovic-Plese|first=Silva|last2=Cortese|first2=Irene|last3=Wandinger|first3=Klaus-Peter|last4=McFarland|first4=Henry F.|last5=Martin|first5=Roland|date=2001-10-15|title=CD4+CD28– costimulation-independent T cells in multiple sclerosis|url=https://doi.org/10.1172/JCI200112516|journal=Journal of Clinical Investigation|language=en|volume=108|issue=8|pages=1185–1194|doi=10.1172/jci12516|issn=0021-9738|pmc=PMC209525|pmid=11602626}}</ref><ref>{{Cite journal|last=Tena|first=Jaime García De|last2=Manzano|first2=Luis|last3=Leal|first3=Juan Carlos|last4=Antonio|first4=Esther San|last5=Sualdea|first5=Verónica|last6=Álvarez-Mon|first6=Melchor|date=2004-03-01|title=Active Crohn's Disease Patients Show a Distinctive Expansion of Circulating Memory CD4+CD45RO+CD28null T Cells|url=https://link.springer.com/article/10.1023/B:JOCI.0000019784.20191.7f|journal=Journal of Clinical Immunology|language=en|volume=24|issue=2|pages=185–196|doi=10.1023/B:JOCI.0000019784.20191.7f|issn=0271-9142}}</ref><ref>{{Cite journal|last=Tena|first=Jaime García De|last2=Manzano|first2=Luis|last3=Leal|first3=Juan Carlos|last4=Antonio|first4=Esther San|last5=Sualdea|first5=Verónica|last6=Álvarez-Mon|first6=Melchor|date=2004-03-01|title=Active Crohn's Disease Patients Show a Distinctive Expansion of Circulating Memory CD4+CD45RO+CD28null T Cells|url=https://link.springer.com/article/10.1023/B:JOCI.0000019784.20191.7f|journal=Journal of Clinical Immunology|language=en|volume=24|issue=2|pages=185–196|doi=10.1023/B:JOCI.0000019784.20191.7f|issn=0271-9142}}</ref>
+Blockade of K<sub>v</sub>1.3 channels in these chronically-activated T cells suppresses calcium signaling, cytokine production (interferon gamma, interleukin-2, interleukin 17), and cell proliferation.<ref name="Kv1.32">{{cite journal|last1=Beeton|first1=C|last2=Wulff|first2=H|last3=Standifer|first3=NE|last4=Azam|first4=P|last5=Mullen|first5=KM|last6=Pennington|first6=MW|last7=Kolski-Andreaco|first7=A|last8=Wei|first8=E|last9=Grino|first9=A|year=2006|title=Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859943/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=103|issue=46|page=17414–17419|doi=10.1073/pnas.0605136103|last10=Counts|first10=DR|last11=Wang|first11=PH|last12=LeeHealey|first12=CJ|last13=Andrews|first13=BS|last14=Sankaranarayanan|first14=A|last15=Homerick|first15=D|last16=Roeck|first16=WW|last17=Tehranzadeh|first17=J|last18=Stanhope|first18=KL|last19=Zimin|first19=P|last20=Havel|first20=PJ|last21=Griffey|first21=S|last22=Knaus|first22=HG|last23=Nepom|first23=GT|last24=Gutman|first24=GA|last25=Calabresi|first25=PA|last26=Chandy|first26=KG|month=November 14,}}</ref><ref name=":75" /><ref name=":142">{{Cite journal|last=Chi|first=Victor|last2=Pennington|first2=Michael W.|last3=Norton|first3=Raymond S.|last4=Tarcha|first4=Eric J.|last5=Londono|first5=Luz M.|last6=Sims-Fahey|first6=Brian|last7=Upadhyay|first7=Sanjeev K.|last8=Lakey|first8=Jonathan T.|last9=Iadonato|first9=Shawn|date=2012-03|title=Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases|url=http://linkinghub.elsevier.com/retrieve/pii/S0041010111002479|journal=Toxicon|volume=59|issue=4|pages=529–546|doi=10.1016/j.toxicon.2011.07.016|issn=0041-0101|pmc=PMC3397671|pmid=21867724}}</ref><ref name=":212">{{Cite journal|last=Rashid|first=M. Harunur|last2=Heinzelmann|first2=Germano|last3=Huq|first3=Redwan|last4=Tajhya|first4=Rajeev B.|last5=Chang|first5=Shih Chieh|last6=Chhabra|first6=Sandeep|last7=Pennington|first7=Michael W.|last8=Beeton|first8=Christine|last9=Norton|first9=Raymond S.|date=2013-11-07|title=A Potent and Selective Peptide Blocker of the Kv1.3 Channel: Prediction from Free-Energy Simulations and Experimental Confirmation|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078712|journal=PLOS ONE|language=en|volume=8|issue=11|pages=e78712|doi=10.1371/journal.pone.0078712|issn=1932-6203|pmc=PMC3820677|pmid=24244345}}</ref><ref name=":222" /><ref name=":23" /><ref name=":24" /><ref name=":25" /> Effector memory T cells that are CD28<sup>+</sup> are refractory to suppression by K<sub>v</sub>1.3 blockers when they are co-stimulated by anti-CD3 and anti-CD28 antibodies, but are sensitive to suppression when stimulated by anti-CD3 antibodies alone.<ref name=":25" /> <i>In vivo</i>, ShK-186 paralyzes effector-memory T cells at the site of an inflammatory delayed type hypersensitivity response and prevents these T cells from activating in the inflamed tissue.<ref name=":5">{{Cite journal|last=Matheu|first=Melanie P.|last2=Beeton|first2=Christine|last3=Garcia|first3=Adriana|last4=Chi|first4=Victor|last5=Rangaraju|first5=Srikant|last6=Safrina|first6=Olga|last7=Monaghan|first7=Kevin|last8=Uemura|first8=Marc I.|last9=Li|first9=Dan|date=2008-10-17|title=Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732399/|journal=Immunity|volume=29|issue=4|pages=602–614|doi=10.1016/j.immuni.2008.07.015|issn=1074-7613|pmc=PMC2732399|pmid=18835197}}</ref> In contrast, ShK-186 does not affect the homing and motility of naive and T<sub>CM</sub> cells to and within lymph nodes, most likely because these cells express the K<sub href="Help:CS1 errors#parameter_ignored">Ca</sub>3.1 channel and are therefore protected from the effect of K<sub href="Category:Pages with citations using unsupported parameters">v</sub>1.3 blockade.<ref name=":5" />
+== Effects on microglia ==
+K<sub href="International Standard Serial Number">v</sub>1.3 plays an important role in microglial activation.<ref>{{Cite journal|last=Khanna|first=R.|last2=Roy|first2=L.|last3=Zhu|first3=X.|last4=Schlichter|first4=L. C.|date=April 2001|title=K+ channels and the microglial respiratory burst|url=https://www.ncbi.nlm.nih.gov/pubmed/11245596|journal=American Journal of Physiology. Cell Physiology|volume=280|issue=4|pages=C796–806|doi=10.1152/ajpcell.2001.280.4.C796|issn=0363-6143|pmid=11245596}}</ref><ref>{{Cite journal|last=Fordyce|first=Christopher B.|last2=Jagasia|first2=Ravi|last3=Zhu|first3=Xiaoping|last4=Schlichter|first4=Lyanne C.|date=2005-08-03|title=Microglia Kv1.3 Channels Contribute to Their Ability to Kill Neurons|url=http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.1251-05.2005|journal=Journal of Neuroscience|volume=25|issue=31|pages=7139–7149|doi=10.1523/jneurosci.1251-05.2005}}</ref><ref>{{Cite journal|last=Nguyen|first=Hai M.|last2=Grössinger|first2=Eva M.|last3=Horiuchi|first3=Makoto|last4=Davis|first4=Kyle W.|last5=Jin|first5=Lee-Way|last6=Maezawa|first6=Izumi|last7=Wulff|first7=Heike|date=2016-10-03|title=Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia|url=http://doi.wiley.com/10.1002/glia.23078|journal=Glia|language=en|volume=65|issue=1|pages=106–121|doi=10.1002/glia.23078|issn=0894-1491|pmc=PMC5113690|pmid=27696527}}</ref><ref>{{Cite journal|last=Nguyen|first=Hai M.|last2=Blomster|first2=Linda V.|last3=Christophersen|first3=Palle|last4=Wulff|first4=Heike|date=2017-07-04|title=Potassium channel expression and function in microglia: Plasticity and possible species variations|url=https://www.ncbi.nlm.nih.gov/pubmed/28277939|journal=Channels (Austin, Tex.)|volume=11|issue=4|pages=305–315|doi=10.1080/19336950.2017.1300738|issn=1933-6969|pmc=PMC5555259|pmid=28277939}}</ref> ShK-223, an analogue of ShK-186, decreased lipopolysaccharide (LPS) induced focal adhesion formation by microglia, reversed LPS-induced inhibition of microglial migration, and inhibited LPS-induced upregulation of EH domain containing protein 1 (EHD1), a protein involved in microglia trafficking.<ref>{{Cite journal|last=Rangaraju|first=Srikant|last2=Raza|first2=Syed Ali|last3=Pennati|first3=Andrea|last4=Deng|first4=Qiudong|last5=Dammer|first5=Eric B.|last6=Duong|first6=Duc|last7=Pennington|first7=Michael W.|last8=Tansey|first8=Malu G.|last9=Lah|first9=James J.|date=2017-06-26|title=A systems pharmacology-based approach to identify novel Kv1.3 channel-dependent mechanisms in microglial activation|url=https://doi.org/10.1186/s12974-017-0906-6|journal=Journal of Neuroinflammation|volume=14|pages=128|doi=10.1186/s12974-017-0906-6|issn=1742-2094|pmc=PMC5485721|pmid=28651603}}</ref> Increased K<sub>v</sub>1.3 expression was reported in microglia in Alzheimer plaques.<ref>{{Cite journal|last=Srikant|first=Rangaraju,|last2=Marla|first2=Gearing,|last3=Lee-Way|first3=Jin,|last4=Allan|first4=Levey,|date=2015-01-01|title=Potassium Channel Kv1.3 Is Highly Expressed by Microglia in Human Alzheimer's Disease|url=http://www.medra.org/servlet/aliasResolver?alias=iospress&genre=article&issn=1387-2877&volume=44&issue=3&spage=797&doi=10.3233/JAD-141704|journal=Journal of Alzheimer's Disease|language=en|volume=44|issue=3|doi=10.3233/jad-141704|issn=1387-2877|pmc=PMC4402159|pmid=25362031}}</ref> K<sub>v</sub>1.3 inhibitors may have use in the management of Alzheimer’s disease, as reported in a proof-of-concept study in which a small molecule K<sub>v</sub>1.3 blocker (PAP-1) alleviated Alzheimer’s disease-like characteristics in a mouse model of AD.<ref>{{Cite journal|last=Maezawa|first=Izumi|last2=Nguyen|first2=Hai M|last3=Di Lucente|first3=Jacopo|last4=Jenkins|first4=David Paul|last5=Singh|first5=Vikrant|last6=Hilt|first6=Silvia|last7=Kim|first7=Kyoungmi|last8=Rangaraju|first8=Srikant|last9=Levey|first9=Allan I|date=2017-12-18|title=Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer’s disease: preclinical proof of concept|url=https://academic.oup.com/brain/article/141/2/596/4759461|journal=Brain|language=en|volume=141|issue=2|pages=596–612|doi=10.1093/brain/awx346|issn=0006-8950|pmc=PMC5837198|pmid=29272333}}</ref>
 == Toxicity ==