1932

Abstract

The identification of a gain-of-function mutation in as the cause of Timothy syndrome, a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted roles for the L-type voltage-gated Ca2+ channel Ca1.2 in nonexcitable cells. Previous studies in cells and animal models had suggested that several voltage-gated Ca2+ channels (VGCCs) regulated critical signaling events in various cell types that are not expected to support action potentials, but definitive data were lacking. VGCCs occupy a special position among ion channels, uniquely able to translate membrane excitability into the cytoplasmic Ca2+ changes that underlie the cellular responses to electrical activity. Yet how these channels function in cells not firing action potentials and what the consequences of their actions are in nonexcitable cells remain critical questions. The development of new animal and cellular models and the emergence of large data sets and unbiased genome screens have added to our understanding of the unanticipated roles for VGCCs in nonexcitable cells. Here, we review current knowledge of VGCC regulation and function in nonexcitable tissues and cells, with the goal of providing a platform for continued investigation.

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2021-02-10
2024-04-21
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Literature Cited

  1. 1. 
    Yue DT. 2004. The dawn of high-resolution structure for the queen of ion channels. Neuron 42:357–59
    [Google Scholar]
  2. 2. 
    Hille B. 2001. Ion Channels of Excitable Membranes Oxford, UK: Oxford Univ. Press
  3. 3. 
    Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P et al. 2004. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31
    [Google Scholar]
  4. 4. 
    Catterall WA. 2011. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol. 3:a003947
    [Google Scholar]
  5. 5. 
    Catterall WA, Lenaeus MJ, Gamal El-Din TM 2020. Structure and pharmacology of voltage-gated sodium and calcium channels. Annu. Rev. Pharmacol. Toxicol. 60:133–54
    [Google Scholar]
  6. 6. 
    Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y et al. 2000. Nomenclature of voltage-gated calcium channels. Neuron 25:533–35
    [Google Scholar]
  7. 7. 
    Wu J, Yan Z, Li Z, Qian X, Lu S et al. 2016. Structure of the voltage-gated calcium channel Cav1.1 at 3.6 Å resolution. Nature 537:191–96
    [Google Scholar]
  8. 8. 
    Yang J, Ellinor PT, Sather WA, Zhang JF, Tsien RW 1993. Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels. Nature 366:158–61
    [Google Scholar]
  9. 9. 
    Lipscombe D, Andrade A. 2015. Calcium channel CaVα1 splice isoforms—tissue specificity and drug action. Curr. Mol. Pharmacol. 8:22–31
    [Google Scholar]
  10. 10. 
    Ma Y, Kobrinsky E, Marks AR 1995. Cloning and expression of a novel truncated calcium channel from non-excitable cells. J. Biol. Chem. 270:483–93
    [Google Scholar]
  11. 11. 
    Kotturi MF, Jefferies WA. 2005. Molecular characterization of L-type calcium channel splice variants expressed in human T lymphocytes. Mol. Immunol. 42:1461–74
    [Google Scholar]
  12. 12. 
    Dolphin AC. 2018. Voltage-gated calcium channel α2δ subunits: an assessment of proposed novel roles. F1000Research 7: https://doi.org/10.12688/f1000research.16104.1
    [Crossref] [Google Scholar]
  13. 13. 
    Buraei Z, Yang J. 2010. The β subunit of voltage-gated Ca2+ channels. Physiol. Rev. 90:1461–506
    [Google Scholar]
  14. 14. 
    Yang L, Katchman A, Kushner J, Kushnir A, Zakharov SI et al. 2019. Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking. J. Clin. Investig. 129:647–58
    [Google Scholar]
  15. 15. 
    Liu G, Papa A, Katchman AN, Zakharov SI, Roybal D et al. 2020. Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics. Nature 577:695–700
    [Google Scholar]
  16. 16. 
    Ben-Johny M, Yue DT. 2014. Calmodulin regulation (calmodulation) of voltage-gated calcium channels. J. Gen. Physiol. 143:679–92
    [Google Scholar]
  17. 17. 
    Dolphin AC. 2016. Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology. J. Physiol. 594:5369–90
    [Google Scholar]
  18. 18. 
    Andronache Z, Ursu D, Lehnert S, Freichel M, Flockerzi V, Melzer W 2007. The auxiliary subunit γ1 of the skeletal muscle L-type Ca2+ channel is an endogenous Ca2+ antagonist. PNAS 104:17885–90
    [Google Scholar]
  19. 19. 
    Fatt P, Katz B. 1953. The electrical properties of crustacean muscle fibres. J. Physiol. 120:171–204
    [Google Scholar]
  20. 20. 
    Alcover A, Weiss MJ, Daley JF, Reinherz EL 1986. The T11 glycoprotein is functionally linked to a calcium channel in precursor and mature T-lineage cells. PNAS 83:2614–18
    [Google Scholar]
  21. 21. 
    Yamaguchi DT, Hahn TJ, Iida-Klein A, Kleeman CR, Muallem S 1987. Parathyroid hormone-activated calcium channels in an osteoblast-like clonal osteosarcoma cell line. cAMP-dependent and cAMP-independent calcium channels. J. Biol. Chem. 262:7711–18
    [Google Scholar]
  22. 22. 
    Chesnoy-Marchais D, Fritsch J. 1988. Voltage-gated sodium and calcium currents in rat osteoblasts. J. Physiol. 398:291–311
    [Google Scholar]
  23. 23. 
    Guggino SE, Lajeunesse D, Wagner JA, Snyder SH 1989. Bone remodeling signaled by a dihydropyridine- and phenylalkylamine-sensitive calcium channel. PNAS 86:2957–60
    [Google Scholar]
  24. 24. 
    Guggino SE, Wagner JA, Snowman AM, Hester LD, Sacktor B, Snyder SH 1988. Phenylalkylamine-sensitive calcium channels in osteoblast-like osteosarcoma cells. Characterization by ligand binding and single channel recordings. J. Biol. Chem. 263:10155–61
    [Google Scholar]
  25. 25. 
    Caffrey JM, Farach-Carson MC. 1989. Vitamin D3 metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells. J. Biol. Chem. 264:20265–74
    [Google Scholar]
  26. 26. 
    Meszaros JG, Karin NJ, Akanbi K, Farach-Carson MC 1996. Down-regulation of L-type Ca2+ channel transcript levels by 1,25-dihyroxyvitamin D3 osteoblastic cells express L-type α1C Ca2+ channel isoforms. J. Biol. Chem. 271:32981–85
    [Google Scholar]
  27. 27. 
    Findeisen F, Minor DL Jr 2009. Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation. J. Gen. Physiol. 133:327–43
    [Google Scholar]
  28. 28. 
    Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB et al. 2005. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. PNAS 102:8089–96
    [Google Scholar]
  29. 29. 
    Lachmann A, Torre D, Keenan AB, Jagodnik KM, Lee HJ et al. 2018. Massive mining of publicly available RNA-seq data from human and mouse. Nat. Commun. 9:1366
    [Google Scholar]
  30. 30. 
    Ramachandran KV, Hennessey JA, Barnett AS, Yin X, Stadt HA et al. 2013. Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development. J. Clin. Investig. 123:1638–46
    [Google Scholar]
  31. 31. 
    Panagiotakos G, Haveles C, Arjun A, Petrova R, Rana A et al. 2019. Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome. eLife 8:e51037
    [Google Scholar]
  32. 32. 
    Tang ZZ, Sharma S, Zheng S, Chawla G, Nikolic J, Black DL 2011. Regulation of the mutually exclusive exons 8a and 8 in the CaV1.2 calcium channel transcript by polypyrimidine tract-binding protein. J. Biol. Chem. 286:10007–16
    [Google Scholar]
  33. 33. 
    Libby P. 2002. Inflammation in atherosclerosis. Nature 420:868–74
    [Google Scholar]
  34. 34. 
    Kolodgie FD, Burke AP, Nakazawa G, Virmani R 2007. Is pathologic intimal thickening the key to understanding early plaque progression in human atherosclerotic disease?. Arterioscler. Thromb. Vasc. Biol. 27:986–89
    [Google Scholar]
  35. 35. 
    Henry PD, Bentley KI. 1981. Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine. J. Clin. Investig. 68:1366–69
    [Google Scholar]
  36. 36. 
    Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB et al. 2000. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 102:1503–10
    [Google Scholar]
  37. 37. 
    Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M et al. 2004. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. The CAMELOT study: a randomized controlled trial. JAMA 292:2217–25
    [Google Scholar]
  38. 38. 
    Weber MA, Jamerson K, Bakris GL, Weir MR, Zappe D et al. 2013. Effects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trial. Lancet 381:537–45
    [Google Scholar]
  39. 39. 
    Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW 1990. Retardation of angiographic progression of coronary artery disease by nifedipine. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). Lancet 335:1109–13
    [Google Scholar]
  40. 40. 
    Napoli C, Chiariello M, Palumbo G, Ambrosio G 1996. Calcium-channel blockers inhibit human low-density lipoprotein oxidation by oxygen radicals. Cardiovasc. Drugs Ther. 10:417–24
    [Google Scholar]
  41. 41. 
    Das R, Burke T, Van Wagoner DR, Plow EF 2009. L-type calcium channel blockers exert an antiinflammatory effect by suppressing expression of plasminogen receptors on macrophages. Circ. Res. 105:167–75
    [Google Scholar]
  42. 42. 
    Guauque-Olarte S, Messika-Zeitoun D, Droit A, Lamontagne M, Tremblay-Marchand J et al. 2015. Calcium signaling pathway genes RUNX2 and CACNA1C are associated with calcific aortic valve disease. Circ. Cardiovasc. Genet. 8:812–22
    [Google Scholar]
  43. 43. 
    Kaden JJ, Dempfle CE, Grobholz R, Fischer CS, Vocke DC et al. 2005. Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc. Pathol. 14:80–87
    [Google Scholar]
  44. 44. 
    Dorn GW 2nd 2013. Shared genetic risk for sclerosis of valves and vessels. N. Engl. J. Med. 368:569–70
    [Google Scholar]
  45. 45. 
    Verhiel S, Piatkowski de Grzymala A, van der Hulst R 2015. Mechanism of action, efficacy, and adverse events of calcium antagonists in hypertrophic scars and keloids: a systematic review. Dermatol. Surg. 41:1343–50
    [Google Scholar]
  46. 46. 
    Nakaoka H, Miyauchi S, Miki Y 1995. Proliferating activity of dermal fibroblasts in keloids and hypertrophic scars. Acta Derm. Venereol. 75:102–4
    [Google Scholar]
  47. 47. 
    Fujiwara M, Muragaki Y, Ooshima A 2005. Keloid-derived fibroblasts show increased secretion of factors involved in collagen turnover and depend on matrix metalloproteinase for migration. Br. J. Dermatol. 153:295–300
    [Google Scholar]
  48. 48. 
    Okada Y, Tsuchiya W, Yada T 1982. Calcium channel and calcium pump involved in oscillatory hyperpolarizing responses of L-strain mouse fibroblasts. J. Physiol. 327:449–61
    [Google Scholar]
  49. 49. 
    Lee RC, Ping JA. 1990. Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J. Surg. Res. 49:463–66
    [Google Scholar]
  50. 50. 
    Akat K, Borggrefe M, Kaden JJ 2009. Aortic valve calcification: basic science to clinical practice. Heart 95:616–23
    [Google Scholar]
  51. 51. 
    Li J, Zhao L, Ferries IK, Jiang L, Desta MZ et al. 2010. Skeletal phenotype of mice with a null mutation in Cav 1.3 L-type calcium channel. J. Musculoskelet. Neuronal Interact. 10:180–87
    [Google Scholar]
  52. 52. 
    Yang SN, Berggren PO. 2006. The role of voltage-gated calcium channels in pancreatic β-cell physiology and pathophysiology. Endocr. Rev. 27:621–76
    [Google Scholar]
  53. 53. 
    Marcantoni A, Vandael DH, Mahapatra S, Carabelli V, Sinnegger-Brauns MJ et al. 2010. Loss of Cav1.3 channels reveals the critical role of L-type and BK channel coupling in pacemaking mouse adrenal chromaffin cells. J. Neurosci. 30:491–504
    [Google Scholar]
  54. 54. 
    Zaidi M, Yuen T, Sun L, Rosen CJ 2018. Regulation of skeletal homeostasis. Endocr. Rev. 39:701–18
    [Google Scholar]
  55. 55. 
    Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P et al. 2015. Tissue-based map of the human proteome. Science 347:1260419
    [Google Scholar]
  56. 56. 
    Beggs MR, Lee JJ, Busch K, Raza A, Dimke H et al. 2019. TRPV6 and Cav1.3 mediate distal small intestine calcium absorption before weaning. Cell. Mol. Gastroenterol. Hepatol. 8:625–42
    [Google Scholar]
  57. 57. 
    Atsuta Y, Tomizawa RR, Levin M, Tabin CJ 2019. L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development. PNAS 116:21592–601
    [Google Scholar]
  58. 58. 
    Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ 2002. Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33:77–80
    [Google Scholar]
  59. 59. 
    Danielsson BR, Reiland S, Rundqvist E, Danielson M 1989. Digital defects induced by vasodilating agents: relationship to reduction in uteroplacental blood flow. Teratology 40:351–58
    [Google Scholar]
  60. 60. 
    Alabdulrazzaq F, Koren G. 2012. Fetal safety of calcium channel blockers. Can. Fam. Phys. 58:746–47
    [Google Scholar]
  61. 61. 
    Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B et al. 1996. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am. J. Obstet. Gynecol. 174:823–28
    [Google Scholar]
  62. 62. 
    Cao C, Ren Y, Barnett AS, Mirando AJ, Rouse D et al. 2017. Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss. JCI Insight 2:e95512
    [Google Scholar]
  63. 63. 
    Lin SS, Tzeng BH, Lee KR, Smith RJ, Campbell KP, Chen CC 2014. Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage. PNAS 111:E1990–98
    [Google Scholar]
  64. 64. 
    Cao C, Oswald AB, Fabella BA, Ren Y, Rodriguiz R et al. 2019. The CaV1.2 L-type calcium channel regulates bone homeostasis in the middle and inner ear. Bone 125:160–68
    [Google Scholar]
  65. 65. 
    Bett GC, Lis A, Wersinger SR, Baizer JS, Duffey ME, Rasmusson RL 2012. A mouse model of Timothy syndrome: a complex autistic disorder resulting from a point mutation in Cav1.2. N. Am. J. Med. Sci. 5:135–40
    [Google Scholar]
  66. 66. 
    Yucel G, Altindag B, Gomez-Ospina N, Rana A, Panagiotakos G et al. 2013. State-dependent signaling by Cav1.2 regulates hair follicle stem cell function. Genes Dev 27:1217–22
    [Google Scholar]
  67. 67. 
    Ebert AM, McAnelly CA, Srinivasan A, Linker JL, Horne WA, Garrity DM 2008. Ca2+ channel-independent requirement for MAGUK family CACNB4 genes in initiation of zebrafish epiboly. PNAS 105:198–203
    [Google Scholar]
  68. 68. 
    Burgess DL, Jones JM, Meisler MH, Noebels JL 1997. Mutation of the Ca2+ channel β subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell 88:385–92
    [Google Scholar]
  69. 69. 
    Dung HC. 1977. Deficiency in the thymus-dependent immunity in “lethargic” mutant mice. Transplantation 23:39–43
    [Google Scholar]
  70. 70. 
    Badou A, Jha MK, Matza D, Mehal WZ, Freichel M et al. 2006. Critical role for the β regulatory subunits of Cav channels in T lymphocyte function. PNAS 103:15529–34
    [Google Scholar]
  71. 71. 
    Jha MK, Badou A, Meissner M, McRory JE, Freichel M et al. 2009. Defective survival of naive CD8+ T lymphocytes in the absence of the β3 regulatory subunit of voltage-gated calcium channels. Nat. Immunol. 10:1275–82
    [Google Scholar]
  72. 72. 
    Jha A, Singh AK, Weissgerber P, Freichel M, Flockerzi V et al. 2015. Essential roles for Cavβ2 and Cav1 channels in thymocyte development and T cell homeostasis. Sci. Signal. 8:ra103
    [Google Scholar]
  73. 73. 
    Omilusik K, Priatel JJ, Chen X, Wang YT, Xu H et al. 2011. The Cav1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Immunity 35:349–60
    [Google Scholar]
  74. 74. 
    Niemeyer BA, Hoth M. 2011. Excitable T cells: Cav1.4 channel contributions and controversies. Immunity 35:315–17
    [Google Scholar]
  75. 75. 
    Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH et al. 2002. The human genome browser at UCSC. Genome Res 12:996–1006
    [Google Scholar]
  76. 76. 
    Gonzalez DAS, Cheli VT, Zamora NN, Lama TN, Spreuer V et al. 2017. Conditional deletion of the L-type calcium channel Cav1.2 in NG2-positive cells impairs remyelination in mice. J. Neurosci. 37:10038–51
    [Google Scholar]
  77. 77. 
    Fields RD. 2008. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. Neuroscientist 14:540–43
    [Google Scholar]
  78. 78. 
    Swanson JB, de Micheli AJ, Disser NP, Martinez LM, Walker NR et al. 2019. A single-cell transcriptional atlas identifies extensive heterogeneity in the cellular composition of tendons. bioRxiv 801266. https://doi.org/10.1101/801266
    [Crossref]
  79. 79. 
    Disser NP, Ghahramani GC, Swanson JB, Wada S, Chao ML et al. 2020. Widespread diversity in the transcriptomes of functionally divergent limb tendons. J. Physiol. 598:1537–50
    [Google Scholar]
  80. 80. 
    Liu H, Xu J, Liu CF, Lan Y, Wylie C, Jiang R 2015. Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. J. Orthop. Res. 33:840–48
    [Google Scholar]
  81. 81. 
    Westenbroek RE, Anderson NL, Byers MR 2004. Altered localization of Cav1.2 (L-type) calcium channels in nerve fibers, Schwann cells, odontoblasts, and fibroblasts of tooth pulp after tooth injury. J. Neurosci. Res. 75:371–83
    [Google Scholar]
  82. 82. 
    Davidson RM, Guo L. 2000. Calcium channel current in rat dental pulp cells. J. Membr. Biol. 178:21–30
    [Google Scholar]
  83. 83. 
    Laugel-Haushalter V, Morkmued S, Stoetzel C, Geoffroy V, Muller J et al. 2018. Genetic evidence supporting the role of the calcium channel, CACNA1S, in tooth cusp and root patterning. Front. Physiol. 9:1329
    [Google Scholar]
  84. 84. 
    Jonsson L, Magnusson TE, Thordarson A, Jonsson T, Geller F et al. 2018. Rare and common variants conferring risk of tooth agenesis. J. Dent. Res. 97:515–22
    [Google Scholar]
  85. 85. 
    Sun W, Chi S, Li Y, Ling S, Tan Y et al. 2019. The mechanosensitive Piezo1 channel is required for bone formation. eLife 8:e47454
    [Google Scholar]
  86. 86. 
    Li X, Han L, Nookaew I, Mannen E, Silva MJ et al. 2019. Stimulation of Piezo1 by mechanical signals promotes bone anabolism. eLife 8:e49631
    [Google Scholar]
  87. 87. 
    Wu J, Lewis AH, Grandl J 2017. Touch, tension, and transduction—the function and regulation of Piezo ion channels. Trends Biochem. Sci. 42:57–71
    [Google Scholar]
  88. 88. 
    Lee W, Leddy HA, Chen Y, Lee SH, Zelenski NA et al. 2014. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. PNAS 111:E5114–22
    [Google Scholar]
  89. 89. 
    Back M, Gasser TC, Michel JB, Caligiuri G 2013. Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovasc. Res. 99:232–41
    [Google Scholar]
  90. 90. 
    Cosman F, Morrow B, Kopal M, Bilezikian JP 1989. Stimulation of inositol phosphate formation in ROS 17/2.8 cell membranes by guanine nucleotide, calcium, and parathyroid hormone. J. Bone Min. Res. 4:413–20
    [Google Scholar]
  91. 91. 
    Santillan G, Baldi C, Katz S, Vazquez G, Boland R 2004. Evidence that TRPC3 is a molecular component of the 1α,25(OH)2D3-activated capacitative calcium entry (CCE) in muscle and osteoblast cells. J. Steroid Biochem. Mol. Biol. 89–90:291–95
    [Google Scholar]
  92. 92. 
    Lieberherr M, Grosse B, Kachkache M, Balsan S 1993. Cell signaling and estrogens in female rat osteoblasts: a possible involvement of unconventional nonnuclear receptors. J. Bone Min. Res. 8:1365–76
    [Google Scholar]
  93. 93. 
    Mermelstein PG, Becker JB, Surmeier DJ 1996. Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor. J. Neurosci. 16:595–604
    [Google Scholar]
  94. 94. 
    Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D et al. 2017. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol. Rev. 97:1045–87
    [Google Scholar]
  95. 95. 
    Filardo E, Quinn J, Pang Y, Graeber C, Shaw S et al. 2007. Activation of the novel estrogen receptor G protein-coupled receptor 30 (GPR30) at the plasma membrane. Endocrinology 148:3236–45
    [Google Scholar]
  96. 96. 
    Edelman A, Fritsch J, Balsan S 1986. Short-term effects of PTH on cultured rat osteoblasts: changes in membrane potential. Am. J. Physiol. 251:C483–90
    [Google Scholar]
  97. 97. 
    Krey JF, Pasca SP, Shcheglovitov A, Yazawa M, Schwemberger R et al. 2013. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat. Neurosci. 16:201–9
    [Google Scholar]
  98. 98. 
    Yang T, Colecraft HM. 2013. Regulation of voltage-dependent calcium channels by RGK proteins. Biochim. Biophys. Acta 1828:1644–54
    [Google Scholar]
  99. 99. 
    Hatzoglou A, Ader I, Splingard A, Flanders J, Saade E et al. 2007. Gem associates with Ezrin and acts via the Rho-GAP protein Gmip to down-regulate the Rho pathway. Mol. Biol. Cell 18:1242–52
    [Google Scholar]
  100. 100. 
    Ward Y, Yap SF, Ravichandran V, Matsumura F, Ito M et al. 2002. The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J. Cell Biol. 157:291–302
    [Google Scholar]
  101. 101. 
    Maguire J, Santoro T, Jensen P, Siebenlist U, Yewdell J, Kelly K 1994. Gem: an induced, immediate early protein belonging to the Ras family. Science 265:241–44
    [Google Scholar]
  102. 102. 
    Ricker E, Chowdhury L, Yi W, Pernis AB 2016. The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Research 5:2295
    [Google Scholar]
  103. 103. 
    Wemhoner K, Friedrich C, Stallmeyer B, Coffey AJ, Grace A et al. 2015. Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome. J. Mol. Cell. Cardiol. 80:186–95
    [Google Scholar]
  104. 104. 
    Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A et al. 2015. Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death. Circ. Arrhythm. Electrophysiol. 8:1122–32
    [Google Scholar]
  105. 105. 
    Adler A, Novelli V, Amin AS, Abiusi E, Care M et al. 2020. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation 141:418–28
    [Google Scholar]
  106. 106. 
    Giudicessi JR, Rohatgi RK, Tester DJ, Ackerman MJ 2020. Variant frequency and clinical phenotype call into question the nature of minor, nonsyndromic long-QT syndrome-susceptibility gene-disease associations. Circulation 141:495–97
    [Google Scholar]
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