N-type calcium channel

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Illustration of the major elements in a prototypical synapse. Synapses allow nerve cells to communicate with one another through axons and dendrites, converting electrical impulses into chemical signals.
Neuron A (transmitting) to neuron B (receiving) 1. Mitochondrion 2. Synaptic vesicle with neurotransmitters 3. Autoreceptor 4. Synapse with neurotransmitter released (serotonin) 5. Postsynaptic receptors activated by neuro-transmitter (induction of a postsynaptic potential) 6. Calcium channel 7. Exocytosis of a vesicle 8. Recaptured neurotransmitter

N-type calcium channels are voltage gated calcium channels that are distributed throughout the entire body. These channels are high voltage activated channels composed of alpha-1B subunits.[1] The alpha subunit forms the pore through which the calcium enters and helps to determine most of the channel's properties. The alpha subunit is also known as the calcium channel/voltage dependent/N type, alpha 1 subunit (CACNA1B), or Cav2.2 which is used in therapeutic processes), which in humans is encoded by the CACNA1B gene.[1] They also contain associated subunits such as β1, β3, β4, α2δ, and possibly γ.[2] These channels are known for their importance in the nervous system. They play a small role in the migration of immature neurons before the establishment of their mature synapses, and they are critically involved in the release of neurotransmitters, which is also similar to another type of calcium channels, known as P-type calcium channels.[2] N-type calcium channels are targets for the development of drugs to relieve chronic and neuropathic pain. They are also used for the treatment of hypertension, Autism Spectrum Disorder, Osteoarthritis, and other medical diagnoses. Additionally, N-type calcium channels have known functions in the kidney, and heart. There are many known N-type calcium channel blockers, but the most notable blocker are ω-Conotoxins. Blockers, like ω-Conotoxins, can interfere with many different therapeutic processes.[3]

Structure[edit]

N-type calcium channel structure

In addition to the α1 subunit, the following subunits are present in the N-type calcium channel:

  • α2δ – CACNA2D1, CACNA2D2
[4] N-type calcium channel

Function[edit]

N-type calcium channels are highly known for their function in the nervous system, but they are also involved with the function of the heart and kidneys.[5][6] They are important in neurotransmitter release because they are localized at the synaptic terminals.[7] When calcium flows into N-type calcium channels due to an action potential, it triggers the fusion of the secretory vesicles. Studies on the cardiovascular system reveal that ω-Conotoxin is introduced causing there to be no more release of norepinephrine, and this shows that only the N-type calcium channel, and not the P/Q/L type calcium channels are involved in the release of norepinephrine.[5] In the Kidneys, N-type calcium channels reduce glomerular pressure through dilation of arterioles when the channel is blocked.[6] The inhibition of this channel by calcium channel blockers can lead to renal microcirculation. N-type calcium channels have been shown to play a part in the localization of neurite growth in the sympathetic nervous system and the skin and spinal cord. The neurite outgrowth was shown to be inhibited through an interaction between laminin and the 11th loop of the n-type calcium channel structure.[8] It has been suggested that neuritis outgrowth is inhibited by the influx of calcium through the growth cone, and this happens when the Cav2.2 subunit comes in contact with laminin 2, and in response can induce a stretch activation of the N-type calcium channel.[8]

Blockers[edit]

Mutation studies[edit]

The N-type calcium channel when mutated can lead to problems in its function, and can also lead to clinical problems.

Clinical significance[edit]

N-type calcium channels have been connected to a variety of different clinical diagnoses. They are most commonly linked to therapeutic treatment of chronic pain. Studies have shown that the intrathecal injection of calcium channel inhibitors such as Ziconotide, to block the N-type calcium channels, have produced alleviation of intractable pain.[9] The use of blockers to inhibit the N-type calcium channels have produced alleviation of chronic pain from a variety of different diseases. For example, blockade of the N-type calcium channel is a potential therapeutic strategy for the treatment of alcoholism.[10] Studies have also shown that N-type peptide blockers have been used to relieve pain that results from osteoarthritis, hypertension, diabetic neuropathy,[11] and cancer.[12] The use of intrathecally injected N-type channel blockers has proven to be more beneficial than common opioid remedies since there are less negative side effects associated. The alteration of N-type calcium channels in therapeutic processes occurs in four major ways; through the blockage of N-type calcium channel peptides, interference of the flow of ions through the channel itself, activation of G-protein coupled signaling, and interference of the G-protein pathways.[13] N-type calcium channels have also been associated with several known diseases as well. For example, mutations in the CACNA1B gene have been associated with Myoclonus-Dystonia syndrome .[14] Duplication of the CACNA1B gene has also been linked to cases of the Autism Spectrum Disorder.[15]

References[edit]

  1. ^ a b Williams ME, Brust PF, Feldman DH, Patthi S, Simerson S, Maroufi A, McCue AF, Veliçelebi G, Ellis SB, Harpold MM (July 1992). "Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel". Science. 257 (5068): 389–95. PMID 1321501. doi:10.1126/science.1321501. 
  2. ^ a b "Voltage-dependent calcium channel, N-type, alpha-1 subunit". InterPro. EMBL-EBI. 
  3. ^ Adams DJ, Berecki G (July 2013). "Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels". Biochimica et Biophysica Acta. 1828 (7): 1619–28. PMID 23380425. doi:10.1016/j.bbamem.2013.01.019. 
  4. ^ "Neuroscience News". Wikimedia Commons. 
  5. ^ a b Molderings GJ, Likungu J, Göthert M (February 2000). "N-Type calcium channels control sympathetic neurotransmission in human heart atrium". Circulation. 101 (4): 403–7. PMID 10653832. doi:10.1161/01.cir.101.4.403. 
  6. ^ a b Hayashi K, Wakino S, Sugano N, Ozawa Y, Homma K, Saruta T (February 2007). "Ca2+ channel subtypes and pharmacology in the kidney". Circulation Research. 100 (3): 342–53. PMID 17307972. doi:10.1161/01.RES.0000256155.31133.49. 
  7. ^ Weber AM, Wong FK, Tufford AR, Schlichter LC, Matveev V, Stanley EF (2010). "N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release". Nature Neuroscience. 13 (11): 1348–50. PMID 20953196. doi:10.1038/nn.2657. Lay summaryNeuroScience: Plus Biology. 
  8. ^ a b Weiss N (May 2008). "The N-type voltage-gated calcium channel: when a neuron reads a map". The Journal of Neuroscience. 28 (22): 5621–2. PMID 18509022. doi:10.1523/JNEUROSCI.1538-08.2008. 
  9. ^ Dray A, Read SJ (May 2007). "Arthritis and pain. Future targets to control osteoarthritis pain". Arthritis Research & Therapy. 9 (3): 212. PMC 2206352Freely accessible. PMID 17561993. doi:10.1186/ar2178. 
  10. ^ Newton PM, Zeng L, Wang V, Connolly J, Wallace MJ, Kim C, Shin HS, Belardetti F, Snutch TP, Messing RO (November 2008). "A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement". The Journal of Neuroscience. 28 (45): 11712–9. PMC 3045811Freely accessible. PMID 18987207. doi:10.1523/JNEUROSCI.3621-08.2008. 
  11. ^ Javed S, Petropoulos IN, Alam U, Malik RA (January 2015). "Treatment of painful diabetic neuropathy". Therapeutic Advances in Chronic Disease. 6 (1): 15–28. PMC 4269610Freely accessible. PMID 25553239. doi:10.1177/2040622314552071. 
  12. ^ Bruel BM, Burton AW (December 2016). "Intrathecal Therapy for Cancer-Related Pain". Pain Medicine. 17 (12): 2404–2421. PMID 28025375. doi:10.1093/pm/pnw060. 
  13. ^ Zamponi GW, Striessnig J, Koschak A, Dolphin AC (October 2015). "The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential". Pharmacological Reviews. 67 (4): 821–70. PMC 4630564Freely accessible. PMID 26362469. doi:10.1124/pr.114.009654. 
  14. ^ Groen JL, Andrade A, Ritz K, Jalalzadeh H, Haagmans M, Bradley TE, Jongejan A, Verbeek DS, Nürnberg P, Denome S, Hennekam RC, Lipscombe D, Baas F, Tijssen MA (February 2015). "CACNA1B mutation is linked to unique myoclonus-dystonia syndrome". Human Molecular Genetics. 24 (4): 987–93. PMC 4817404Freely accessible. PMID 25296916. doi:10.1093/hmg/ddu513. 
  15. ^ Heyes S, Pratt WS, Rees E, Dahimene S, Ferron L, Owen MJ, Dolphin AC (November 2015). "Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders". Progress in Neurobiology. 134: 36–54. PMC 4658333Freely accessible. PMID 26386135. doi:10.1016/j.pneurobio.2015.09.002. 

Further reading[edit]