N-type calcium channel

N-type calcium channels, also called Ca_v2.2 channels, are voltage gated calcium channels that are localized primarily on the nerve terminals and dendrites as well as neuroendocrine cells.{{cite journal | vauthors = Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J| title=Voltage-gated calcium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database | journal=IUPHAR/BPS Guide to Pharmacology CITE | publisher=Edinburgh University Library | volume=2019 | issue=4 | date=2019-09-16 | issn=2633-1020 | doi=10.2218/gtopdb/f80/2019.4 | page=| doi-access=free }} 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. 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.{{cite web|title=Voltage-dependent calcium channel, N-type, alpha-1 subunit|url=https://www.ebi.ac.uk/interpro/entry/IPR005447|website=InterPro|publisher=EMBL-EBI}}{{cite journal |vauthors=Heyes S, Pratt WS, Rees E, Dahimene S, Ferron L, Owen MJ, Dolphin AC |title=Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders |journal=Prog Neurobiol |volume=134 |pages=36–54 |date=November 2015 |pmid=26386135 |pmc=4658333 |doi=10.1016/j.pneurobio.2015.09.002 }} 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.{{cite journal | vauthors = Adams DJ, Berecki G | title = Mechanisms of conotoxin inhibition of N-type (Ca(v)2.2) calcium channels | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1828 | issue = 7 | pages = 1619–28 | date = July 2013 | pmid = 23380425 | doi = 10.1016/j.bbamem.2013.01.019 | doi-access = free }}

File:Crystal Structure of N-Type Channel.png

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 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.{{cite web|last1=EMBL-EBI|first1=InterPro|title=Voltage-dependent calcium channel, N-type, alpha-1 subunit (IPR005447) < InterPro < EMBL-EBI|url=http://www.ebi.ac.uk/interpro/entry/IPR005447|website=www.ebi.ac.uk|language=en}}

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 synaptic terminals.{{cite journal | vauthors = Weber AM, Wong FK, Tufford AR, Schlichter LC, Matveev V, Stanley EF | title = N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release | journal = Nature Neuroscience | volume = 13 | issue = 11 | pages = 1348–50 | year = 2010 | pmid = 20953196 | doi = 10.1038/nn.2657 | s2cid = 205433301 }}*{{lay source |template = cite web|vauthors = |url = http://neurosciencenews.com/n-type-calcium-channel-neurotransmitter-release/|title = Single N-type Calcium Channel May Enable Neurotransmitter Release|date = November 2, 2010 |website = NeuroScience: Plus Biology}} 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.{{cite journal | vauthors = Molderings GJ, Likungu J, Göthert M | title = N-Type calcium channels control sympathetic neurotransmission in human heart atrium | journal = Circulation | volume = 101 | issue = 4 | pages = 403–7 | date = February 2000 | pmid = 10653832 | doi=10.1161/01.cir.101.4.403| doi-access = free }}

In the kidneys, blocking of N-type calcium channels reduce glomerular pressure through dilation of arterioles.{{cite journal | vauthors = Hayashi K, Wakino S, Sugano N, Ozawa Y, Homma K, Saruta T | title = Ca2+ channel subtypes and pharmacology in the kidney | journal = Circulation Research | volume = 100 | issue = 3 | pages = 342–53 | date = February 2007 | pmid = 17307972 | doi = 10.1161/01.RES.0000256155.31133.49 | doi-access = free }}

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.{{cite journal | vauthors = Weiss N | title = The N-type voltage-gated calcium channel: when a neuron reads a map | journal = The Journal of Neuroscience | volume = 28 | issue = 22 | pages = 5621–2 | date = May 2008 | pmid = 18509022 | doi = 10.1523/JNEUROSCI.1538-08.2008 | pmc = 6670785 }} 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.

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. Loss-of-function CACNA1B mutations were found to be present in progressive epilepsy-dyskinesia.{{cite journal |vauthors=Gorman KM, Meyer E, Grozeva D, Spinelli E, McTague A, Sanchis-Juan A, Carss KJ, Bryant E, Reich A, Schneider AL, Pressler RM, Simpson MA, Debelle GD, Wassmer E, Morton J, Sieciechowicz D, Jan-Kamsteeg E, Paciorkowski AR, King MD, Cross JH, Poduri A, Mefford HC, Scheffer IE, Haack TB, McCullagh G, Millichap JJ, Carvill GL, Clayton-Smith J, Maher ER, Raymond FL, Kurian MA |display-authors = 6|title=Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia |journal=Am J Hum Genet |volume=104 |issue=5 |pages=948–956 |date=May 2019 |pmid=30982612 |pmc=6507039 |doi=10.1016/j.ajhg.2019.03.005 }}

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 peptides, interference of the flow of ions through the channel itself, activation of G-protein coupled signaling, and interference of the G-protein pathways.{{cite journal | vauthors = Zamponi GW, Striessnig J, Koschak A, Dolphin AC | title = The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential | journal = Pharmacological Reviews | volume = 67 | issue = 4 | pages = 821–70 | date = October 2015 | pmid = 26362469 | doi = 10.1124/pr.114.009654 | ref = Zamponi | pmc=4630564}} 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.{{cite journal | vauthors = Dray A, Read SJ | title = Arthritis and pain. Future targets to control osteoarthritis pain | journal = Arthritis Research & Therapy | volume = 9 | issue = 3 | pages = 212 | date = May 2007 | pmid = 17561993 | pmc = 2206352 | doi = 10.1186/ar2178 | doi-access = free }} 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.{{cite journal | vauthors = Newton PM, Zeng L, Wang V, Connolly J, Wallace MJ, Kim C, Shin HS, Belardetti F, Snutch TP, Messing RO | title = A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement | journal = The Journal of Neuroscience | volume = 28 | issue = 45 | pages = 11712–9 | date = November 2008 | pmid = 18987207 | doi = 10.1523/JNEUROSCI.3621-08.2008 | ref = Newton | pmc=3045811}}

Blockers

File:Ziconotide 1DW5.pngIn 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.{{Cite journal|date=2013-07-01|title=Mechanisms of conotoxin inhibition of N-type (Cav2.2) calcium channels|journal=Biochimica et Biophysica Acta (BBA) - Biomembranes|language=en|volume=1828|issue=7|pages=1619–1628|doi=10.1016/j.bbamem.2013.01.019|pmid=23380425|issn=0005-2736|last1=Adams|first1=David J.|last2=Berecki|first2=Géza|doi-access=free}}

List of N-type Calcium channel blockers:

ω-Conotoxins
Cadmium
Caroverine
Cilnidipine
Desipramine{{cite journal |vauthors=Benjamin ER, Pruthi F, Olanrewaju S, Shan S, Hanway D, Liu X, Cerne R, Lavery D, Valenzano KJ, Woodward RM, Ilyin VI |title=Pharmacological characterization of recombinant N-type calcium channel (Cav2.2) mediated calcium mobilization using FLIPR |journal=Biochem Pharmacol |volume=72 |issue=6 |pages=770–82 |date=September 2006 |pmid=16844100 |doi=10.1016/j.bcp.2006.06.003 }}
Gabapentin nonselectively inhibits N-type calcium channels by attaching to auxiliary α2δ subunit
Levetiracetam
Lamotrigine
Nicardipine
NP078585
Phenibut{{Cite journal |last=Zvejniece |first=Liga |last2=Vavers |first2=Edijs |last3=Svalbe |first3=Baiba |last4=Veinberg |first4=Grigory |last5=Rizhanova |first5=Kristina |last6=Liepins |first6=Vilnis |last7=Kalvinsh |first7=Ivars |last8=Dambrova |first8=Maija |date=October 2015 |title=R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects |url=https://pubmed.ncbi.nlm.nih.gov/26234470/ |journal=Pharmacology, Biochemistry, and Behavior |volume=137 |pages=23–29 |doi=10.1016/j.pbb.2015.07.014 |issn=1873-5177 |pmid=26234470}}
Piracetam{{cite journal |vauthors=Bravo-Martínez J, Arenas I, Vivas O, Rebolledo-Antúnez S, Vázquez-García M, Larrazolo A, García DE |title=A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons |journal=Exp Biol Med (Maywood) |volume=237 |issue=10 |pages=1209–18 |date=October 2012 |pmid=23045722 |doi=10.1258/ebm.2012.012128 |s2cid=25909697 }}
Pregabalin nonselectively inhibits N-type calcium channels by attaching to auxiliary α2δ subunit
TROX-1
Ziconotide, a synthetic version of one of conotoxins