N-type calcium channel

Calcium channel, voltage-dependent, N type, alpha 1B subunit
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2LCM​
Identifiers
Symbols	CACNA1B ; BIII; CACNL1A5; CACNN; Cav2.2; DYT23
External IDs	OMIM: 601012 MGI: 88296 HomoloGene: 20184 IUPHAR: 533 ChEMBL: 4478 GeneCards: CACNA1B Gene
Gene ontology Molecular function • voltage-gated calcium channel activity • calcium ion binding • protein binding • ATP binding • protein C-terminus binding • high voltage-gated calcium channel activity Cellular component • plasma membrane • voltage-gated calcium channel complex • dendrite • neuronal cell body Biological process • transport • calcium ion transport • synaptic transmission • neurotransmitter secretion • locomotory behavior • regulation of heart contraction • regulation of blood pressure • ion transmembrane transport • regulation of ion transmembrane transport • response to pain • membrane depolarization • regulation of calcium ion transport • calcium ion import • calcium ion transmembrane transport • membrane depolarization during action potential Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	774	12287
Ensembl	ENSG00000148408	ENSMUSG00000004113
UniProt	Q00975	O55017
RefSeq (mRNA)	NM_000718	NM_001042528
RefSeq (protein)	NP_000709	NP_001035993
Location (UCSC)	Chr 9: 137.88 – 138.12 Mb	Chr 2: 24.6 – 24.76 Mb
PubMed search

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

The N-type calcium channel is a type of voltage-dependent calcium channel. As with other sub-types of voltage-gated calcium channel, the α₁ subunit forms the pore through which calcium enters the cell and determines most of the channel's properties. The α₁ subunit is also known as the calcium channel, voltage-dependent, N type, alpha 1B subunit (CACNA1B) or Ca_v2.2^[1] which in humans is encoded by the CACNA1B gene.^[2][3][4]

Clinical significance

Mutations in CACNA1B are associated to Myoclonus-Dystonia syndrome .^[5]

Structure

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

• α₂δ – CACNA2D1, CACNA2D2
• β₁ – CACNB1
• β₃ – CACNB3
• β₄ – CACNB4

Function

N-type ('N' for "Neural-Type" ) calcium channels are found primarily at presynaptic terminals and are involved in neurotransmission.^[6] Strong depolarization by an action potential causes these channels to open and allow influx of Ca²⁺, initiating vesicle fusion and release of stored neurotransmitter. N-type channels are blocked by ω-conotoxin.^[1]

Therapeutic Potential

Blockade of the N-type calcium channel is a potential therapeutic strategy for the treatment of alcoholism.^[7][8] Blockade of N-type calcium channels in sensory neurons has therapeutic potential for the treatment of certain types of pain, particularly neuropathic pain. The peptide N-type calcium channel blocker ziconotide is given intrathecally for intractable pain.

Blockers

• ω-Conotoxins
• Ziconotide
• Caroverine
• Cilnidipine
• NP078585^[7]
• TROX-1
• Cadmium
• Gabapentin^[9]
• Levetiracetam^[10]
• Lamotrigine^[11]
• Nicardipine^[12]

References

1. Williams ME, Brust PF, Feldman DH, Patthi S, Simerson S, Maroufi A, McCue AF, Veliçelebi G, Ellis SB, Harpold MM (Jul 1992). "Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel". Science 257 (5068): 389–95. Bibcode:1992Sci...257..389W. doi:10.1126/science.1321501. PMID 1321501.
2. "Entrez Gene: CACNA1B calcium channel, voltage-dependent, N type, alpha 1B subunit".
3. Diriong S, Lory P, Williams ME, Ellis SB, Harpold MM, Taviaux S (Dec 1995). "Chromosomal localization of the human genes for alpha 1A, alpha 1B, and alpha 1E voltage-dependent Ca2+ channel subunits". Genomics 30 (3): 605–9. doi:10.1006/geno.1995.1284. PMID 8825650.
4. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (Dec 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.
5. 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 (Feb 2015). "CACNA1B mutation is linked to unique myoclonus-dystonia syndrome". Human Molecular Genetics 24 (4): 987–93. doi:10.1093/hmg/ddu513. PMID 25296916.
6. Kurihara T, Tanabe T (Apr 2003). "N-type Ca2+ channel". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica 121 (4): 211–22. doi:10.1254/fpj.121.211. PMID 12777840.
7. Newton PM, Zeng L, Wang V, Connolly J, Wallace MJ, Kim C, Shin HS, Belardetti F, Snutch TP, Messing RO (Nov 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. Lay summary – Psychology Today.
8. Newton PM, Messing RO (2009). "The N-type calcium channel is a novel target for treating alcohol use disorders". Channels 3 (2): 77–81. doi:10.4161/chan.3.2.8037. PMID 19372737.
9. Vega-Hernández A, Felix R (Apr 2002). "Down-regulation of N-type voltage-activated Ca2+ channels by gabapentin". Cellular and Molecular Neurobiology 22 (2): 185–90. PMID 12363200.
10. Lukyanetz EA, Shkryl VM, Kostyuk PG (Jan 2002). "Selective blockade of N-type calcium channels by levetiracetam". Epilepsia 43 (1): 9–18. doi:10.1046/j.1528-1157.2002.24501.x. PMID 11879381.
11. Wang SJ, Huang CC, Hsu KS, Tsai JJ, Gean PW (Nov 1996). "Inhibition of N-type calcium currents by lamotrigine in rat amygdalar neurones". NeuroReport 7 (18): 3037–40. doi:10.1097/00001756-199611250-00048. PMID 9116235.
12. Li SN, Bräter M, Andreas K (Feb 1999). "Nicardipine inhibits N-type calcium channels in dbcAMP-differentiated neuroblastoma x glioma hybrid cells (NG 108-15 cells)". Acta Pharmacologica Sinica 20 (2): 117–120. PMID 10437156.

Further reading

• Mould J, Yasuda T, Schroeder CI, Beedle AM, Doering CJ, Zamponi GW, Adams DJ, Lewis RJ (Aug 2004). "The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels". The Journal of Biological Chemistry 279 (33): 34705–14. doi:10.1074/jbc.M310848200. PMID 15166237.
• Park SY, Park YT, Kim KE, Rhee MC, Cho HJ, Kim DS (Apr 2002). "A direct repeat of N-type Ca2+ channel alpha1B gene functions as a negative regulatory element in HeLa cells". Molecules and Cells 13 (2): 341–6. PMID 12018859.
• Calabrese B, Tabarean IV, Juranka P, Morris CE (Nov 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 (Mar 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. PMID 19065143.
• Castiglioni AJ, Raingo J, Lipscombe D (Oct 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 (Dec 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.
• Yokoyama CT, Myers SJ, Fu J, Mockus SM, Scheuer T, Catterall WA (Jan 2005). "Mechanism of SNARE protein binding and regulation of Cav2 channels by phosphorylation of the synaptic protein interaction site". Molecular and Cellular Neurosciences 28 (1): 1–17. doi:10.1016/j.mcn.2004.08.019. PMID 15607937.
• Maeno-Hikichi Y, Chang S, Matsumura K, Lai M, Lin H, Nakagawa N, Kuroda S, Zhang JF (May 2003). "A PKC epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels". Nature Neuroscience 6 (5): 468–75. doi:10.1038/nn1041. PMID 12665800.
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (Nov 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.
• Li D, Wang F, Lai M, Chen Y, Zhang JF (Feb 2005). "A protein phosphatase 2calpha-Ca2+ channel complex for dephosphorylation of neuronal Ca2+ channels phosphorylated by protein kinase C". The Journal of Neuroscience 25 (8): 1914–23. doi:10.1523/JNEUROSCI.4790-04.2005. PMID 15728831.
• Butcher AJ, Leroy J, Richards MW, Pratt WS, Dolphin AC (Jul 2006). "The importance of occupancy rather than affinity of CaV(beta) subunits for the calcium channel I-II linker in relation to calcium channel function". The Journal of Physiology 574 (Pt 2): 387–98. doi:10.1113/jphysiol.2006.109744. PMC 1817768. PMID 16627564.
• Stotz SC, Barr W, McRory JE, Chen L, Jarvis SE, Zamponi GW (Jan 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 (Aug 2002). "Synaptic targeting of N-type calcium channels in hippocampal neurons". The Journal of Neuroscience 22 (16): 6939–52. PMC 3307533. PMID 12177192.
• Peng S, Hajela RK, Atchison WD (Dec 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 (Oct 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. 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.
• Coppola T, Magnin-Luthi S, Perret-Menoud V, Gattesco S, Schiavo G, Regazzi R (Aug 2001). "Direct interaction of the Rab3 effector RIM with Ca2+ channels, SNAP-25, and synaptotagmin". The Journal of Biological Chemistry 276 (35): 32756–62. doi:10.1074/jbc.M100929200. PMID 11438518.
• Johnson JM, Castle J, Garrett-Engele P, Kan Z, Loerch PM, Armour CD, Santos R, Schadt EE, Stoughton R, Shoemaker DD (Dec 2003). "Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays". Science 302 (5653): 2141–4. Bibcode:2003Sci...302.2141J. doi:10.1126/science.1090100. PMID 14684825.
• Agler HL, Evans J, Tay LH, Anderson MJ, Colecraft HM, Yue DT (Jun 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.

External links

• CACNA1B protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• N-Type Calcium Channel at the US National Library of Medicine Medical Subject Headings (MeSH)