N-type calcium channel
N-type calcium channels also called Cav2.2 channels are
Structure
N-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
In addition to the α1B subunit encoded by CACNA1B gene, the following auxiliary subunits are present in the N-type calcium channel:
- α2δ – encoded by either one of two genes CACNA2D1, CACNA2D2
- β – encoded by either one of four genes CACNB1, CACNB2, CACNB3, CACNB4
Function
N-type calcium channels are important in neurotransmitter release because they are localized at the
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
A 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
The alteration of N-type calcium channels in therapeutic processes occurs in four major ways; through the blockage of N-type calcium channel
Blockers
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
- Gabapentin nonselectively inhibits N-type calcium channels by attaching to auxiliary α2δ subunit
- Levetiracetam
- Lamotrigine
- Nicardipine
- NP078585
- Pregabalin nonselectively inhibits N-type calcium channels by attaching to auxiliary α2δ subunit
- TROX-1
- Ziconotide, a synthetic version of one of conotoxins
References
- ISSN 2633-1020.
- ^ a b "Voltage-dependent calcium channel, N-type, alpha-1 subunit". InterPro. EMBL-EBI.
- ^ PMID 26386135.
- PMID 23380425.
- ^ EMBL-EBI, InterPro. "Voltage-dependent calcium channel, N-type, alpha-1 subunit (IPR005447) < InterPro < EMBL-EBI". www.ebi.ac.uk.
- S2CID 205433301.*Lay summary in: "Single N-type Calcium Channel May Enable Neurotransmitter Release". NeuroScience: Plus Biology. November 2, 2010.
- PMID 10653832.
- PMID 17307972.
- ^ PMID 18509022.
- PMID 30982612.
- PMID 26362469.
- PMID 17561993.
- PMID 18987207.
- PMID 23380425.
- PMID 16844100.
- S2CID 25909697.
Further reading
- Calabrese B, Tabarean IV, Juranka P, Morris CE (November 2002). "Mechanosensitivity of N-type calcium channel currents". Biophysical Journal. 83 (5): 2560–74. 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. PMID 19065143.
- Castiglioni AJ, Raingo J, 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. 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. 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. 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. 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. 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. 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. 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. PMID 15953418.