N-type calcium channels also called Cav2.2 channels are voltage gated calcium channels that are localized primarily on the nerve terminals and dendrites as well as neuroendocrine cells.[1] The calcium N-channel consists of several subunits: the primary subunit α1B and the auxiliary subunits α2δ and β. The α1B subunit forms the pore through which the calcium enters and helps to determine most of the channel's properties.[2] These channels play an important role in the neurotransmission during development. In the adult nervous system, N-type calcium channels are critically involved in the release of neurotransmitters, and in pain pathways.[2][3] N-type calcium channels are the target of ziconotide, the drug prescribed to relieve intractable cancer pain. There are many known N-type calcium channel blockers that function to inhibit channel activity, although the most notable blockers are ω-conotoxins.[4]
Structure
editN-type calcium channels are categorized as high threshold-activated channels and seen in the Cav2 gene family. The structure of the N-type calcium channel is very similar to other voltage-dependent channels. The most important part of the channel is the actual pore that is formed by the α1B subunit. This pore is the location of the import of the extracellular ions. The α1B subunit has as many as 2000 amino acid residues within an amino acid sequence with the transmembrane structure with a pore. This is organized into 6 six segments(S1-S6). S1, S2, S3, S5, and S6 are hydrophobic while S4 serves as the voltage-sensor. In addition there is a membrane-associated loop in between S5 and S6. The activity of the pore is modulated by 4 subunits: an intracellular β-subunit, a transmembrane gamma subunit, and complex of alpha-2 and delta subunits.[5]
In addition to the α1B subunit encoded by CACNA1B gene, the following auxiliary subunits are present in the N-type calcium channel:
Function
editN-type calcium channels are important in neurotransmitter release because they are localized at the synaptic terminals.[6] In the peripheral nervous system, N-type channels are known to be involved in the release of many neurotransmitters like glutamate, GABA, acetylcholine, dopamine, and norepinephrine. When extracellular 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 when ω-Conotoxin is introduced, it causes the inhibition of norepinephrine, and this shows that only the N-type calcium channel, not the P/Q/L type calcium channels, are involved in the release of norepinephrine.[7]
In the kidneys, blocking of N-type calcium channels reduce glomerular pressure through dilation of arterioles.[8]
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.[9] It has been suggested that neurites outgrowth is inhibited by the influx of calcium through the growth cone, and this happens when the Cav2.2 channel comes in contact with laminin 2, and in response can induce a stretch activation of the N-type calcium channel.[9]
Mutations
editA rare gain-of-function mutation in CACNA1B gene encoding the α1B subunit of N-type calcium channel was suggested as the cause of several cases of a myoclonus-dystonia syndrome, although this suggestion has been disputed.[3] Loss-of-function CACNA1B mutations were found to be present in progressive epilepsy-dyskinesia.[10]
Clinical significance
editThe 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.[11] Studies have shown that the intrathecal injection of the calcium channel inhibitor ziconotide, to block the N-type calcium channels, have produced alleviation of intractable pain.[12] Blockade of the N-type calcium channel is a potential therapeutic strategy for the treatment of alcoholism. Because prolonged alcohol exposure over time has been known to increase N-type channel function, experiments have shown that using N-type antagonists to decrease channel activity resulted in reduced voluntary consumption of alcohol in mice.[13]
Blockers
edit
In the pain pathway, N-type calcium channels serve to regulate pain signals sent from the peripheral nervous system to Central Nervous System. Although many N-type calcium channels blockers are known, most potent and selective belong to the family of conotoxins.[14]
List of N-type Calcium channel blockers:
- ω-Conotoxins
- Cadmium
- Caroverine
- Cilnidipine
- Desipramine[15]
- Gabapentin nonselectively inhibits N-type calcium channels by attaching to auxiliary α2δ subunit
- Levetiracetam
- Lamotrigine
- Nicardipine
- NP078585
- Phenibut[16]
- Piracetam[17]
- Pregabalin nonselectively inhibits N-type calcium channels by attaching to auxiliary α2δ subunit
- TROX-1
- Ziconotide, a synthetic version of one of conotoxins
References
edit- ^ Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2019-09-16). "Voltage-gated calcium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database". IUPHAR/BPS Guide to Pharmacology CITE. 2019 (4). Edinburgh University Library. doi:10.2218/gtopdb/f80/2019.4. ISSN 2633-1020.
- ^ a b "Voltage-dependent calcium channel, N-type, alpha-1 subunit". InterPro. EMBL-EBI.
- ^ a b 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". Prog Neurobiol. 134: 36–54. doi:10.1016/j.pneurobio.2015.09.002. PMC 4658333. PMID 26386135.
- ^ Adams DJ, Berecki G (July 2013). "Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1828 (7): 1619–28. doi:10.1016/j.bbamem.2013.01.019. PMID 23380425.
- ^ EMBL-EBI, InterPro. "Voltage-dependent calcium channel, N-type, alpha-1 subunit (IPR005447) < InterPro < EMBL-EBI". www.ebi.ac.uk.
- ^ 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. doi:10.1038/nn.2657. PMID 20953196. S2CID 205433301.*Lay summary in: "Single N-type Calcium Channel May Enable Neurotransmitter Release". NeuroScience: Plus Biology. November 2, 2010.
- ^ Molderings GJ, Likungu J, Göthert M (February 2000). "N-Type calcium channels control sympathetic neurotransmission in human heart atrium". Circulation. 101 (4): 403–7. doi:10.1161/01.cir.101.4.403. PMID 10653832.
- ^ 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. doi:10.1161/01.RES.0000256155.31133.49. PMID 17307972.
- ^ 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. doi:10.1523/JNEUROSCI.1538-08.2008. PMC 6670785. PMID 18509022.
- ^ Gorman KM, Meyer E, Grozeva D, Spinelli E, McTague A, Sanchis-Juan A, et al. (May 2019). "Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia". Am J Hum Genet. 104 (5): 948–956. doi:10.1016/j.ajhg.2019.03.005. PMC 6507039. PMID 30982612.
- ^ 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. doi:10.1124/pr.114.009654. PMC 4630564. PMID 26362469.
- ^ Dray A, Read SJ (May 2007). "Arthritis and pain. Future targets to control osteoarthritis pain". Arthritis Research & Therapy. 9 (3): 212. doi:10.1186/ar2178. PMC 2206352. PMID 17561993.
- ^ 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. doi:10.1523/JNEUROSCI.3621-08.2008. PMC 3045811. PMID 18987207.
- ^ Adams, David J.; Berecki, Géza (2013-07-01). "Mechanisms of conotoxin inhibition of N-type (Cav2.2) calcium channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1828 (7): 1619–1628. doi:10.1016/j.bbamem.2013.01.019. ISSN 0005-2736. PMID 23380425.
- ^ Benjamin ER, Pruthi F, Olanrewaju S, Shan S, Hanway D, Liu X, Cerne R, Lavery D, Valenzano KJ, Woodward RM, Ilyin VI (September 2006). "Pharmacological characterization of recombinant N-type calcium channel (Cav2.2) mediated calcium mobilization using FLIPR". Biochem Pharmacol. 72 (6): 770–82. doi:10.1016/j.bcp.2006.06.003. PMID 16844100.
- ^ Zvejniece, Liga; Vavers, Edijs; Svalbe, Baiba; Veinberg, Grigory; Rizhanova, Kristina; Liepins, Vilnis; Kalvinsh, Ivars; Dambrova, Maija (October 2015). "R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacology, Biochemistry, and Behavior. 137: 23–29. doi:10.1016/j.pbb.2015.07.014. ISSN 1873-5177. PMID 26234470.
- ^ Bravo-Martínez J, Arenas I, Vivas O, Rebolledo-Antúnez S, Vázquez-García M, Larrazolo A, García DE (October 2012). "A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons". Exp Biol Med (Maywood). 237 (10): 1209–18. doi:10.1258/ebm.2012.012128. PMID 23045722. S2CID 25909697.
Further reading
edit- Calabrese B, Tabarean IV, Juranka P, Morris CE (November 2002). "Mechanosensitivity of N-type calcium channel currents". Biophysical Journal. 83 (5): 2560–74. Bibcode:2002BpJ....83.2560C. doi:10.1016/S0006-3495(02)75267-3. PMC 1302342. PMID 12414690.
- Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E, Owen MJ, O'Donovan MC (March 2009). "Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk". Molecular Psychiatry. 14 (3): 252–60. doi:10.1038/mp.2008.133. PMC 3970088. PMID 19065143.
- Castiglioni AJ, Raingo J, Lipscombe D (October 2006). "Alternative splicing in the C-terminus of CaV2.2 controls expression and gating of N-type calcium channels". The Journal of Physiology. 576 (Pt 1): 119–34. doi:10.1113/jphysiol.2006.115030. PMC 1995641. PMID 16857708.
- Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (December 2005). "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels". Pharmacological Reviews. 57 (4): 411–25. doi:10.1124/pr.57.4.5. PMID 16382099. S2CID 10386627.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- Stotz SC, Barr W, McRory JE, Chen L, Jarvis SE, Zamponi GW (January 2004). "Several structural domains contribute to the regulation of N-type calcium channel inactivation by the beta 3 subunit". The Journal of Biological Chemistry. 279 (5): 3793–800. doi:10.1074/jbc.M308991200. PMID 14602720.
- Maximov A, Bezprozvanny I (August 2002). "Synaptic targeting of N-type calcium channels in hippocampal neurons". The Journal of Neuroscience. 22 (16): 6939–52. doi:10.1523/JNEUROSCI.22-16-06939.2002. PMC 3307533. PMID 12177192.
- Peng S, Hajela RK, Atchison WD (December 2002). "Characteristics of block by Pb2+ of function of human neuronal L-, N-, and R-type Ca2+ channels transiently expressed in human embryonic kidney 293 cells". Molecular Pharmacology. 62 (6): 1418–30. doi:10.1124/mol.62.6.1418. PMID 12435810.
- Murakami M, Fleischmann B, De Felipe C, Freichel M, Trost C, Ludwig A, Wissenbach U, Schwegler H, Hofmann F, Hescheler J, Flockerzi V, Cavalié A (October 2002). "Pain perception in mice lacking the beta3 subunit of voltage-activated calcium channels". The Journal of Biological Chemistry. 277 (43): 40342–51. doi:10.1074/jbc.M203425200. hdl:10261/310195. PMID 12161429.
- Vitko I, Shcheglovitov A, Baumgart JP, Arias-Olguín II, Murbartián J, Arias JM, Perez-Reyes E (2008). Schwartz A (ed.). "Orientation of the calcium channel beta relative to the alpha(1)2.2 subunit is critical for its regulation of channel activity". PLOS ONE. 3 (10): e3560. Bibcode:2008PLoSO...3.3560V. doi:10.1371/journal.pone.0003560. PMC 2570331. PMID 18958281.
- Agler HL, Evans J, Tay LH, Anderson MJ, Colecraft HM, Yue DT (June 2005). "G protein-gated inhibitory module of N-type (ca(v)2.2) ca2+ channels". Neuron. 46 (6): 891–904. doi:10.1016/j.neuron.2005.05.011. PMID 15953418.