Abstract
Calcium (Ca2+) plays a central role in regulating many cellular processes and influences cell survival. Several mechanisms can disrupt Ca2+ homeostasis to trigger cell death, including oxidative stress, mitochondrial damage, excitotoxicity, neuroinflammation, autophagy, and apoptosis. Voltage-gated Ca2+ channels (VGCCs) act as the main source of Ca2+ entry into electrically excitable cells, such as neurons, and they are also expressed in glial cells such as astrocytes and oligodendrocytes. The dysregulation of VGCC activity has been reported in both Parkinson's disease (PD) and Huntington's (HD). PD and HD are progressive neurodegenerative disorders (NDs) of the basal ganglia characterized by motor impairment as well as cognitive and psychiatric dysfunctions. This review will examine the putative role of neuronal VGCCs in the pathogenesis and treatment of central movement disorders, focusing on PD and HD. The link between basal ganglia disorders and VGCC physiology will provide a framework for understanding the neurodegenerative processes that occur in PD and HD, as well as a possible path towards identifying new therapeutic targets for the treatment of these debilitating disorders.
Keywords: Calcium channels, neurodegenerative disorders, parkinson’s disease, huntington’s disease, basal ganglia and cell death.
Graphical Abstract
[http://dx.doi.org/10.1113/jphysiol.1957.sp005808] [PMID: 13449874]
[http://dx.doi.org/10.1016/0166-2236(95)80030-6] [PMID: 7537420]
[http://dx.doi.org/10.1126/science.7832825] [PMID: 7832825]
[http://dx.doi.org/10.1126/science.2845577] [PMID: 2845577]
[http://dx.doi.org/10.1016/S0143-4160(98)90116-6] [PMID: 9601613]
[http://dx.doi.org/10.1523/JNEUROSCI.17-18-06961.1997] [PMID: 9278532]
[http://dx.doi.org/10.1016/S0896-6273(00)80510-3] [PMID: 9697848]
[http://dx.doi.org/10.1038/351751a0] [PMID: 1648178]
[http://dx.doi.org/10.32607/20758251-2010-2-1-72-80] [PMID: 22649630]
[http://dx.doi.org/10.1038/nrd.2015.5] [PMID: 26542451]
[http://dx.doi.org/10.1016/j.nbd.2011.04.007] [PMID: 21515375]
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.06.006] [PMID: 23891486]
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.015] [PMID: 28391067]
[http://dx.doi.org/10.1177/1759091419856811] [PMID: 31216184]
[http://dx.doi.org/10.1038/s41467-019-12834-x] [PMID: 31704946]
[http://dx.doi.org/10.3389/fnagi.2019.00382] [PMID: 32009942]
[http://dx.doi.org/10.1146/annurev.cellbio.16.1.521] [PMID: 11031246]
[http://dx.doi.org/10.1124/pr.57.4.5] [PMID: 16382099]
[http://dx.doi.org/10.1038/316440a0] [PMID: 2410796]
[http://dx.doi.org/10.1038/nrn3311] [PMID: 22805911]
[http://dx.doi.org/10.1038/346567a0] [PMID: 2165570]
[http://dx.doi.org/10.1016/0304-4157(94)00014-5] [PMID: 7742348]
[http://dx.doi.org/10.1167/iovs.03-0937] [PMID: 14744918]
[http://dx.doi.org/10.1083/jcb.123.4.949] [PMID: 8227151]
[http://dx.doi.org/10.1007/s00441-014-1936-3] [PMID: 24996399]
[http://dx.doi.org/10.1002/cne.21567] [PMID: 18067152]
[http://dx.doi.org/10.1038/32448] [PMID: 9515967]
[http://dx.doi.org/10.1126/science.1357749] [PMID: 1357749]
[http://dx.doi.org/10.1126/science.8388125] [PMID: 8388125]
[http://dx.doi.org/10.1016/0014-5793(87)80073-X] [PMID: 2436945]
[http://dx.doi.org/10.1021/bi981255g] [PMID: 9799496]
[http://dx.doi.org/10.1016/S0896-6273(03)00430-6] [PMID: 12895422]
[http://dx.doi.org/10.1016/j.neuron.2011.02.042] [PMID: 21482359]
[http://dx.doi.org/10.1152/physrev.00018.2002] [PMID: 12506128]
[http://dx.doi.org/10.1523/JNEUROSCI.4305-09.2010] [PMID: 20053892]
[http://dx.doi.org/10.1007/s00249-007-0138-2] [PMID: 17340096]
[http://dx.doi.org/10.1523/JNEUROSCI.23-20-07551.2003] [PMID: 12930793]
[http://dx.doi.org/10.1016/S0896-6273(01)00454-8] [PMID: 11604141]
[http://dx.doi.org/10.1523/JNEUROSCI.0068-12.2012] [PMID: 22764245]
[http://dx.doi.org/10.1111/bph.15498] [PMID: 33871884]
[http://dx.doi.org/10.1523/JNEUROSCI.2781-11.2011] [PMID: 21940446]
[http://dx.doi.org/10.1523/JNEUROSCI.0362-09.2009] [PMID: 19657020]
[http://dx.doi.org/10.1038/aps.2009.24] [PMID: 19343058]
[http://dx.doi.org/10.1016/j.jphs.2020.07.011] [PMID: 32807662]
[http://dx.doi.org/10.1093/function/zqaa027]
[http://dx.doi.org/10.1007/s10495-010-0481-0] [PMID: 20213199]
[http://dx.doi.org/10.1152/jn.01193.2006] [PMID: 17376845]
[http://dx.doi.org/10.1523/JNEUROSCI.1709-07.2007] [PMID: 18057200]
[http://dx.doi.org/10.1146/annurev-biochem-061516-045037] [PMID: 28441057]
[http://dx.doi.org/10.1016/j.bbrc.2004.04.011] [PMID: 15110764]
[http://dx.doi.org/10.1126/scisignal.2000672] [PMID: 20354224]
[http://dx.doi.org/10.1016/S0008-6363(95)00128-X] [PMID: 8595629]
[http://dx.doi.org/10.1097/00005344-200408000-00009] [PMID: 15243301]
[http://dx.doi.org/10.1038/nature09536] [PMID: 21068725]
[http://dx.doi.org/10.1172/JCI95898] [PMID: 29708514]
[http://dx.doi.org/10.1111/j.1749-6632.2010.05634.x] [PMID: 20649555]
[http://dx.doi.org/10.1038/nature05292] [PMID: 17051205]
[http://dx.doi.org/10.1016/j.stemcr.2018.09.006] [PMID: 30344006]
[http://dx.doi.org/10.1074/jbc.M102334200] [PMID: 11500491]
[http://dx.doi.org/10.1016/B978-0-12-813832-8.00013-3]
[http://dx.doi.org/10.3389/fncel.2019.00514] [PMID: 31803024]
[http://dx.doi.org/10.1186/s12974-015-0262-3] [PMID: 25888781]
[http://dx.doi.org/10.1186/s12974-018-1278-2] [PMID: 30205834]
[http://dx.doi.org/10.1186/s12974-020-01930-1] [PMID: 32859212]
[http://dx.doi.org/10.1523/JNEUROSCI.18-07-02321.1998] [PMID: 9502793]
[http://dx.doi.org/10.1016/j.arr.2018.01.001] [PMID: 29339150]
[http://dx.doi.org/10.3389/fnagi.2016.00303] [PMID: 28018215]
[http://dx.doi.org/10.1126/science.277.5334.1990] [PMID: 9302293]
[http://dx.doi.org/10.1126/science.1060627] [PMID: 11431533]
[http://dx.doi.org/10.1002/jnr.22178] [PMID: 19610108]
[http://dx.doi.org/10.1186/s13024-015-0022-y] [PMID: 26159606]
[http://dx.doi.org/10.1073/pnas.2136625100] [PMID: 14657369]
[http://dx.doi.org/10.3389/fmolb.2019.00048] [PMID: 31380390]
[http://dx.doi.org/10.1074/jbc.M109.021956] [PMID: 19638347]
[http://dx.doi.org/10.1038/nchembio.79] [PMID: 18391949]
[http://dx.doi.org/10.1126/science.290.5497.1717] [PMID: 11099404]
[http://dx.doi.org/10.1016/j.biocel.2015.09.010] [PMID: 26429067]
[http://dx.doi.org/10.1038/nrdp.2017.13] [PMID: 28332488]
[http://dx.doi.org/10.1056/NEJM199810083391506] [PMID: 9761807]
[http://dx.doi.org/10.1172/JCI200317575] [PMID: 12531866]
[http://dx.doi.org/10.1186/s13024-016-0097-0] [PMID: 27094865]
[http://dx.doi.org/10.1016/S1474-4422(09)70293-5] [PMID: 19909911]
[http://dx.doi.org/10.1007/978-1-4939-2359-5_12]
[http://dx.doi.org/10.1038/42166] [PMID: 9278044]
[http://dx.doi.org/10.1126/science.1090278] [PMID: 14593171]
[http://dx.doi.org/10.3389/fnins.2019.01399] [PMID: 32038126]
[http://dx.doi.org/10.1096/fj.03-0098fje] [PMID: 14519670]
[http://dx.doi.org/10.1073/pnas.0908005106] [PMID: 19892735]
[http://dx.doi.org/10.1016/j.bpj.2015.11.2520]
[http://dx.doi.org/10.1016/j.brainres.2014.09.046] [PMID: 25446002]
[http://dx.doi.org/10.3389/fnagi.2018.00109] [PMID: 29719505]
[http://dx.doi.org/10.1016/0006-8993(90)91236-A] [PMID: 2257487]
[http://dx.doi.org/10.1093/brain/122.8.1421] [PMID: 10430829]
[http://dx.doi.org/10.1523/JNEUROSCI.4341-06.2007] [PMID: 17234596]
[http://dx.doi.org/10.1093/brain/114.5.2283] [PMID: 1933245]
[http://dx.doi.org/10.1016/j.expneurol.2017.08.001] [PMID: 28780195]
[http://dx.doi.org/10.1152/jn.2000.83.5.3084] [PMID: 10805703]
[http://dx.doi.org/10.1038/nature05865] [PMID: 17558391]
[http://dx.doi.org/10.1152/jn.00486.2004] [PMID: 15486420]
[http://dx.doi.org/10.1074/jbc.M111.269951] [PMID: 21998310]
[http://dx.doi.org/10.1523/JNEUROSCI.3904-14.2015] [PMID: 25855191]
[http://dx.doi.org/10.1016/0306-4522(94)90232-1] [PMID: 7969910]
[http://dx.doi.org/10.1042/BST0340903] [PMID: 17052224]
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021214] [PMID: 30625283]
[http://dx.doi.org/10.1002/ana.21937] [PMID: 20437557]
[http://dx.doi.org/10.1212/01.wnl.0000303818.38960.44] [PMID: 18256367]
[http://dx.doi.org/10.1111/j.1471-4159.2012.07703.x] [PMID: 22356203]
[http://dx.doi.org/10.1016/S0006-8993(96)00917-1] [PMID: 9001722]
[http://dx.doi.org/10.1038/nn.3209] [PMID: 22941107]
[http://dx.doi.org/10.1101/cshperspect.a009290] [PMID: 22762023]
[http://dx.doi.org/10.1523/JNEUROSCI.4742-09.2009] [PMID: 20007466]
[http://dx.doi.org/10.1080/13543776.2018.1541982] [PMID: 30372652]
[http://dx.doi.org/10.18632/oncotarget.17618] [PMID: 28521299]
[http://dx.doi.org/10.1155/2015/697404] [PMID: 26464872]
[http://dx.doi.org/10.1002/mds.870110204] [PMID: 8684382]
[http://dx.doi.org/10.1002/ana.410310412] [PMID: 1375014]
[http://dx.doi.org/10.1016/0092-8674(93)90585-E] [PMID: 8458085]
[http://dx.doi.org/10.1038/ng0893-398] [PMID: 8401589]
[PMID: 22180703]
[http://dx.doi.org/10.1128/MCB.24.18.8195-8209.2004] [PMID: 15340079]
[http://dx.doi.org/10.1086/318207] [PMID: 11133364]
[http://dx.doi.org/10.1093/hmg/ddi407] [PMID: 16278236]
[http://dx.doi.org/10.3174/ajnr.A6168] [PMID: 31467235]
[http://dx.doi.org/10.1111/jnc.14853] [PMID: 31418858]
[http://dx.doi.org/10.3389/fcell.2020.611735] [PMID: 33425919]
[http://dx.doi.org/10.1016/j.bbrc.2004.08.035] [PMID: 15336977]
[http://dx.doi.org/10.1371/journal.pgen.0030082] [PMID: 17500595]
[http://dx.doi.org/10.1016/j.mcn.2005.07.016] [PMID: 16162412]
[http://dx.doi.org/10.1126/science.1191027] [PMID: 20929812]
[http://dx.doi.org/10.1016/j.celrep.2017.03.056] [PMID: 28402855]
[http://dx.doi.org/10.32607/20758251-2014-6-4-40-47] [PMID: 25558393]
[http://dx.doi.org/10.3389/fphys.2015.00337] [PMID: 26635623]
[http://dx.doi.org/10.3389/fcell.2021.625231] [PMID: 33604336]
[http://dx.doi.org/10.1074/jbc.M116.727990] [PMID: 27624941]
[http://dx.doi.org/10.1002/ana.410400110] [PMID: 8687191]
[http://dx.doi.org/10.1111/j.1468-1331.2008.02390.x] [PMID: 19138335]
[http://dx.doi.org/10.1016/B978-0-444-63425-2.00010-6]
[http://dx.doi.org/10.1523/JNEUROSCI.20-24-08987.2000] [PMID: 11124974]
[http://dx.doi.org/10.1002/(SICI)1097-4695(199908)40:2<137:AID-NEU1>3.0.CO;2-A] [PMID: 10413445]
[http://dx.doi.org/10.1002/jnr.490260405] [PMID: 1977925]
[http://dx.doi.org/10.1016/j.neuron.2009.01.033] [PMID: 19409267]
[http://dx.doi.org/10.1038/s41467-018-03111-4] [PMID: 29459792]
[http://dx.doi.org/10.1523/JNEUROSCI.0608-14.2014] [PMID: 25100594]
[http://dx.doi.org/10.1523/ENEURO.0167-17.2017] [PMID: 29177188]
[http://dx.doi.org/10.1523/JNEUROSCI.2946-16.2017] [PMID: 28592699]
[http://dx.doi.org/10.1038/s41467-019-09494-2] [PMID: 31000720]
[http://dx.doi.org/10.1021/acschemneuro.6b00186] [PMID: 27596273]
[http://dx.doi.org/10.1002/mds.23308] [PMID: 20818667]
[http://dx.doi.org/10.1002/mds.25639] [PMID: 24123224]
[http://dx.doi.org/10.1002/acn3.412] [PMID: 28589163]
[http://dx.doi.org/10.7326/M19-2534] [PMID: 32227247]
[http://dx.doi.org/10.1002/acn3.51300] [PMID: 33460320]
[http://dx.doi.org/10.1002/mds.28850] [PMID: 34766657]
[http://dx.doi.org/10.14573/altex.2013.3.275] [PMID: 23861075]
[http://dx.doi.org/10.7326/M20-1023] [PMID: 32227234]
[http://dx.doi.org/10.1523/JNEUROSCI.4129-11.2012] [PMID: 22442066]
[http://dx.doi.org/10.1038/aps.2014.107] [PMID: 25640478]
[http://dx.doi.org/10.1152/jn.00181.2021] [PMID: 34469694]
[http://dx.doi.org/10.1523/JNEUROSCI.08-10-03901.1988] [PMID: 2461437]
[http://dx.doi.org/10.1038/s41593-021-00806-8] [PMID: 33649507]
[http://dx.doi.org/10.1038/s41587-021-00844-4] [PMID: 33623158]
[http://dx.doi.org/10.1093/aje/kwr362] [PMID: 22387374]
[http://dx.doi.org/10.1002/ana.22616] [PMID: 22451203]
[http://dx.doi.org/10.1016/j.biopsych.2008.09.008] [PMID: 18947822]
[http://dx.doi.org/10.1002/mds.23555] [PMID: 21370266]
[http://dx.doi.org/10.1016/j.sleep.2013.05.016] [PMID: 23859128]
[http://dx.doi.org/10.1006/nbdi.1996.0007] [PMID: 9173914]
[http://dx.doi.org/10.1101/cshperspect.a035212] [PMID: 31427373]
[http://dx.doi.org/10.1016/B978-008045046-9.01629-6]
[http://dx.doi.org/10.1016/j.pharmthera.2011.11.006] [PMID: 22133841]
[http://dx.doi.org/10.1046/j.1471-4159.1998.70041532.x] [PMID: 9523570]
[http://dx.doi.org/10.1016/S0306-4522(03)00385-3] [PMID: 12895515]
[http://dx.doi.org/10.1172/JCI46482] [PMID: 21737877]