5-HT6 receptor

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5-hydroxytryptamine (serotonin) receptor 6, G protein-coupled
Identifiers
Symbols HTR6 ; 5-HT6; 5-HT6R
External IDs OMIM601109 MGI1196627 HomoloGene673 IUPHAR: 5-HT6 ChEMBL: 3371 GeneCards: HTR6 Gene
RNA expression pattern
PBB GE HTR6 206944 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3362 15565
Ensembl ENSG00000158748 ENSMUSG00000028747
UniProt P50406 Q9R1C8
RefSeq (mRNA) NM_000871 NM_021358
RefSeq (protein) NP_000862 NP_067333
Location (UCSC) Chr 1:
19.99 – 20.01 Mb
Chr 4:
139.06 – 139.08 Mb
PubMed search [1] [2]

The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).[1] It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission.[1] HTR6 denotes the human gene encoding for the receptor.[2]

Distribution[edit]

The 5-HT6 receptor is expressed almost exclusively in the brain.[3] It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum.[1][4][5] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[3][5][6]

Function[edit]

Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[7][8][9][10] whereas activation enhances GABAergic signaling in a widespread manner.[11] Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]

Despite the 5-HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[11] In parallel with this, 5-HT6 antagonists improve cognition, learning, and memory,[13] and agents such as latrepirdine, Lu AE58054, and SB-742,457 are being developed as novel treatments for Alzheimer's disease and other forms of dementia.[10][14][15] 5-HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.[16][17]

Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.[11][18] Additionally, it can be inferred that 5-HT6 activation likely plays a major role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Ligands[edit]

A large number of selective 5-HT6 ligands have now been developed and this is a productive current area of research.[19][20][21][22][23][24][25]

Full agonists[edit]

Partial Agonists[edit]

  • E-6801[30]
  • E-6837 - partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration[31]

Antagonists[edit]

Genetics[edit]

The receptor is encoded by the HTR6 gene. As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain, and research studies have investigated whether polymorphisms is associated with brain-related variables, such as neuropsychiatric disorders. For example, in 2004 one Chinese study reported an association between the C267T (rs1805054) polymorphism and Alzheimer's disease.[36] Others have studied the polymorphism in relation to Parkinson's disease.[37]

See also[edit]

References[edit]

  1. ^ a b c Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". J. Neurochem. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988. 
  2. ^ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6". 
  3. ^ a b Woolley ML, Marsden CA, Fone KC (February 2004). "5-ht6 receptors". Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. doi:10.2174/1568007043482561. PMID 14965245. 
  4. ^ Ruat M, Traiffort E, Arrang JM, et al. (May 1993). "A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation". Biochemical and Biophysical Research Communications 193 (1): 268–76. doi:10.1006/bbrc.1993.1619. PMID 8389146. 
  5. ^ a b Gérard C, Martres MP, Lefèvre K, et al. (January 1997). "Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system". Brain Research 746 (1-2): 207–19. doi:10.1016/S0006-8993(96)01224-3. PMID 9037500. 
  6. ^ Hamon M, Doucet E, Lefèvre K, et al. (August 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors". Neuropsychopharmacology 21 (2 Suppl): 68S–76S. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491. 
  7. ^ Dawson LA, Nguyen HQ, Li P (May 2000). "In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate". British Journal of Pharmacology 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993. 
  8. ^ Dawson LA, Nguyen HQ, Li P (November 2001). "The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus". Neuropsychopharmacology 25 (5): 662–8. doi:10.1016/S0893-133X(01)00265-2. PMID 11682249. 
  9. ^ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 2004). "5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism". Neuropharmacology 47 (2): 195–204. doi:10.1016/j.neuropharm.2004.03.012. PMID 15223298. 
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  11. ^ a b c d e f Schechter LE, Lin Q, Smith DL, et al. (May 2008). "Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466". Neuropsychopharmacology 33 (6): 1323–35. doi:10.1038/sj.npp.1301503. PMID 17625499. 
  12. ^ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse 51 (2): 158–64. doi:10.1002/syn.10288. PMID 14618683. 
  13. ^ King MV, Marsden CA, Fone KC (September 2008). "A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory". Trends in Pharmacological Sciences 29 (9): 482–92. doi:10.1016/j.tips.2008.07.001. PMID 19086256. 
  14. ^ Geldenhuys WJ, Van der Schyf CJ (2008). "Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry 8 (12): 1035–48. doi:10.2174/156802608785161420. PMID 18691131. 
  15. ^ Geldenhuys WJ, Van der Schyf CJ (July 2009). "The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease". Expert Review of Neurotherapeutics 9 (7): 1073–85. doi:10.1586/ern.09.51. PMID 19589055. 
  16. ^ a b Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 2008). "Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders". Pharmacology & Therapeutics 117 (2): 207–31. doi:10.1016/j.pharmthera.2007.08.006. PMID 18068807. 
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  19. ^ Trani G, Baddeley SM, Briggs MA, Chuang TT, Deeks NJ, Johnson CN, Khazragi AA, Mead TL, Medhurst AD, Milner PH, Quinn LP, Ray AM, Rivers DA, Stean TO, Stemp G, Trail BK, Witty DR (October 2008). "Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists". Bioorg. Med. Chem. Lett. 18 (20): 5698–700. doi:10.1016/j.bmcl.2008.08.010. PMID 18793848. 
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Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.