Advertisement

CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency

  • Ping LiaoEmail author
  • Tuck Wah Soong
Ion Channels, Receptors and Transporters

Abstract

Mutations of human CaV1.2 channel gene were identified only recently. The gain-of-function mutations were found at two mutually exclusive exons in patients with Timothy syndrome (TS). These patients exhibit prolonged QT interval and lethal cardiac arrhythmias. In contrast, the loss-of-function mutations of CaV1.2 channel in patients with Brugada syndrome produce short QT interval that could result in sudden cardiac death. TS patients also suffer from multi-organ dysfunction that includes neurological disorder such as autism and mental retardation reflecting the wide tissue distribution of CaV1.2 channel. Mutations found on different mutually exclusive exons determine the severity of the disease. Unexpectedly, TS patients may develop recurrent infections and bronchitis that suggests a role of CaV1.2 channel in the immune system. Furthermore, recent reports revealed a linkage of CaV1.2 channel polymorphism with multiple central nervous system disorders including bipolar disorder, depression, and schizophrenia. Here, we will discuss how alternative splicing modulates CaV1.2 channelopathy and the role of CaV1.2 channel in both excitable and non-excitable tissues.

Keywords

Ca2+ channels Immune response Electrophysiology Arrhythmia Central nervous system 

Notes

Acknowledgments

This work was supported by grants from National Medical Research Council and Biomedical Research Council of Singapore.

Conflict of interests

None declared.

References

  1. 1.
    Abernethy DR, Soldatov NM (2002) Structure–functional diversity of human L-type Ca2+ channel: perspectives for new pharmacological targets. J Pharmacol Exp Ther 300:724–728CrossRefPubMedGoogle Scholar
  2. 2.
    Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355CrossRefPubMedGoogle Scholar
  3. 3.
    Adams B, Tanabe T (1997) Structural regions of the cardiac Ca channel alpha subunit involved in Ca-dependent inactivation. J Gen Physiol 110:379–389CrossRefPubMedGoogle Scholar
  4. 4.
    Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y et al (2007) Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 115:442–449CrossRefPubMedGoogle Scholar
  5. 5.
    Barrett CF, Tsien RW (2008) The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of Cav1.2L-type calcium channels. Proc Natl Acad Sci U S A 105:2157–2162CrossRefPubMedGoogle Scholar
  6. 6.
    Busquet P, Hetzenauer A, Sinnegger-Brauns MJ, Striessnig J, Singewald N (2008) Role of L-type Ca2+ channel isoforms in the extinction of conditioned fear. Learn Mem 15:378–386CrossRefPubMedGoogle Scholar
  7. 7.
    Cens T, Restituito S, Galas S, Charnet P (1999) Voltage and calcium use the same molecular determinants to inactivate calcium channels. J Biol Chem 274:5483–5490CrossRefPubMedGoogle Scholar
  8. 8.
    Cheng X, Liu J, Asuncion-Chin M, Blaskova E, Bannister JP, Dopico AM, Jaggar JH (2007) A novel Cav1.2 N terminus expressed in smooth muscle cells of resistance size arteries modifies channel regulation by auxiliary subunits. J Biol Chem 282:29211–29221CrossRefPubMedGoogle Scholar
  9. 9.
    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 105:167–175CrossRefPubMedGoogle Scholar
  10. 10.
    Erxleben C, Liao Y, Gentile S, Chin D, Gomez-Alegria C, Mori Y, Birnbaumer L, Armstrong DL (2006) Cyclosporin and Timothy syndrome increase mode 2 gating of Cav1.2 calcium channels through aberrant phosphorylation of S6 helices. Proc Natl Acad Sci U S A 103:3932–3937CrossRefPubMedGoogle Scholar
  11. 11.
    Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J et al (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40:1056–1058CrossRefPubMedGoogle Scholar
  12. 12.
    Gidh-Jain M, Huang B, Jain P, Battula V, el-Sherif N (1995) Reemergence of the fetal pattern of L-type calcium channel gene expression in non infarcted myocardium during left ventricular remodeling. Biochem Biophys Res Commun 216:892–897CrossRefPubMedGoogle Scholar
  13. 13.
    Gomez-Ospina N, Tsuruta F, Barreto-Chang O, Hu L, Dolmetsch R (2006) The C terminus of the L-type voltage-gated calcium channel Cav1.2 encodes a transcription factor. Cell 127:591–606CrossRefPubMedGoogle Scholar
  14. 14.
    Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S, Gordon-Smith K et al (2009) The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. doi: 10.1038/mp.2009.49
  15. 15.
    Gupta S, Salam N, Srivastava V, Singla R, Behera D, Khayyam KU, Korde R, Malhotra P, Saxena R, Natarajan K (2009) Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis. PLoS One 4:e5305CrossRefPubMedGoogle Scholar
  16. 16.
    Halling DB, Aracena-Parks P, Hamilton SL (2006) Regulation of voltage-gated Ca2+ channels by calmodulin. Sci STKE 2006:er1Google Scholar
  17. 17.
    Jacobs A, Knight BP, McDonald KT, Burke MC (2006) Verapamil decreases ventricular tachyarrhythmias in a patient with Timothy syndrome (LQT8). Heart Rhythm 3:967–970CrossRefPubMedGoogle Scholar
  18. 18.
    Kim J, Ghosh S, Nunziato DA, Pitt GS (2004) Identification of the components controlling inactivation of voltage-gated Ca2+ channels. Neuron 41:745–754CrossRefPubMedGoogle Scholar
  19. 19.
    Krug A, Nieratschker V, Markov V, Krach S, Jansen A, Zerres K, Eggermann T, Stocker T, Shah NJ, Treutlein J, Muhleisen TW, Kircher T (2009) Effect of CACNA1C rs1006737 on neural correlates of verbal fluency in healthy individuals. Neuroimage. doi: 10.1016/j.neuroimage.2009.09.028
  20. 20.
    Liao P, Li G, de Yu J, Yong TF, Wang JJ, Wang J, Soong TW (2009) Molecular alteration of Cav1.2 calcium channel in chronic myocardial infarction. Pflugers Arch 458:701–711CrossRefPubMedGoogle Scholar
  21. 21.
    Liao P, Yong TF, Liang MC, Yue DT, Soong TW (2005) Splicing for alternative structures of Cav1.2 Ca2+ channels in cardiac and smooth muscles. Cardiovasc Res 68:197–203CrossRefPubMedGoogle Scholar
  22. 22.
    Liao P, Yu D, Li G, Yong TF, Soon JL, Chua YL, Soong TW (2007) A smooth muscle Cav1.2 calcium channel splice variant underlies hyperpolarized window current and enhanced state-dependent inhibition by nifedipine. J Biol Chem 282:35133–35142CrossRefPubMedGoogle Scholar
  23. 23.
    Liao P, Yu D, Lu S, Tang Z, Liang MC, Zeng S, Lin W, Soong TW (2004) Smooth muscle-selective alternatively spliced exon generates functional variation in Cav1.2 calcium channels. J Biol Chem 279:50329–50335CrossRefPubMedGoogle Scholar
  24. 24.
    Liao P, Zhang HY, Soong TW (2009) Alternative splicing of voltage-gated calcium channels: from molecular biology to disease. Pflugers Arch 458:481–487CrossRefPubMedGoogle Scholar
  25. 25.
    Marks ML, Trippel DL, Keating MT (1995) Long QT syndrome associated with syndactyly identified in females. Am J Cardiol 76:744–745CrossRefPubMedGoogle Scholar
  26. 26.
    Marks ML, Whisler SL, Clericuzio C, Keating M (1995) A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol 25:59–64CrossRefPubMedGoogle Scholar
  27. 27.
    Matza D, Flavell RA (2009) Roles of Cav channels and AHNAK1 in T cells: the beauty and the beast. Immunol Rev 231:257–264CrossRefPubMedGoogle Scholar
  28. 28.
    McKinney BC, Sze W, White JA, Murphy GG (2008) L-type voltage-gated calcium channels in conditioned fear: a genetic and pharmacological analysis. Learn Mem 15:326–334CrossRefPubMedGoogle Scholar
  29. 29.
    McQuillin A, Rizig M, Gurling HM (2007) A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet Genomics 17:605–617CrossRefPubMedGoogle Scholar
  30. 30.
    Reichenbach H, Meister EM, Theile H (1992) The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet. Kinderarztl Prax 60:54–56PubMedGoogle Scholar
  31. 31.
    Schroder E, Byse M, Satin J (2009) L-type calcium channel C terminus autoregulates transcription. Circ Res 104:1373–1381CrossRefPubMedGoogle Scholar
  32. 32.
    Seisenberger C, Specht V, Welling A, Platzer J, Pfeifer A, Kuhbandner S, Striessnig J, Klugbauer N, Feil R, Hofmann F (2000) Functional embryonic cardiomyocytes after disruption of the L-type alpha1C (Cav1.2) calcium channel gene in the mouse. J Biol Chem 275:39193–39199CrossRefPubMedGoogle Scholar
  33. 33.
    Sicouri S, Timothy KW, Zygmunt AC, Glass A, Goodrow RJ, Belardinelli L, Antzelevitch C (2007) Cellular basis for the electrocardiographic and arrhythmic manifestations of Timothy syndrome: effects of ranolazine. Heart Rhythm 4:638–647CrossRefPubMedGoogle Scholar
  34. 34.
    Sinnegger-Brauns MJ, Hetzenauer A, Huber IG, Renstrom E, Wietzorrek G, Berjukov S et al (2004) Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels. J Clin Invest 113:1430–1439PubMedGoogle Scholar
  35. 35.
    Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K et al (2008) Whole-genome association study of bipolar disorder. Mol Psychiatry 13:558–569CrossRefPubMedGoogle Scholar
  36. 36.
    Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A 102:8089–8096CrossRefPubMedGoogle Scholar
  37. 37.
    Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT (2004) Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31CrossRefPubMedGoogle Scholar
  38. 38.
    Stotz SC, Hamid J, Spaetgens RL, Jarvis SE, Zamponi GW (2000) Fast inactivation of voltage-dependent calcium channels. A hinged-lid mechanism? J Biol Chem 275:24575–24582CrossRefPubMedGoogle Scholar
  39. 39.
    Tang ZZ, Hong X, Wang J, Soong TW (2007) Signature combinatorial splicing profiles of rat cardiac- and smooth-muscle Cav1.2 channels with distinct biophysical properties. Cell Calcium 41:417–428CrossRefPubMedGoogle Scholar
  40. 40.
    Tang ZZ, Liang MC, Lu S, Yu D, Yu CY, Yue DT, Soong TW (2004) Transcript scanning reveals novel and extensive splice variations in human l-type voltage-gated calcium channel, Cav1.2 alpha1 subunit. J Biol Chem 279:44335–44343CrossRefPubMedGoogle Scholar
  41. 41.
    Tang ZZ, Liao P, Li G, Jiang FL, Yu D, Hong X, Yong TF, Tan G, Lu S, Wang J, Soong TW (2008) Differential splicing patterns of L-type calcium channel Cav1.2 subunit in hearts of Spontaneously Hypertensive Rats and Wistar Kyoto Rats. Biochim Biophys Acta 1783:118–130CrossRefPubMedGoogle Scholar
  42. 42.
    Thiel WH, Chen B, Hund TJ, Koval OM, Purohit A, Song LS, Mohler PJ, Anderson ME (2008) Proarrhythmic defects in Timothy syndrome require calmodulin kinase II. Circulation 118:2225–2234CrossRefPubMedGoogle Scholar
  43. 43.
    Tiwari S, Zhang Y, Heller J, Abernethy DR, Soldatov NM (2006) Atherosclerosis-related molecular alteration of the human Cav1.2 calcium channel α1c subunit. Proc Natl Acad Sci U S A 103:17024–17029CrossRefPubMedGoogle Scholar
  44. 44.
    Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS et al (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–533CrossRefPubMedGoogle Scholar
  45. 45.
    Welling A, Ludwig A, Zimmer S, Klugbauer N, Flockerzi V, Hofmann F (1997) Alternatively spliced IS6 segments of the alpha 1C gene determine the tissue- specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type Ca2+ channels. Circ Res 81:526–532PubMedGoogle Scholar
  46. 46.
    White JA, McKinney BC, John MC, Powers PA, Kamp TJ, Murphy GG (2008) Conditional forebrain deletion of the L-type calcium channel Cav1.2 disrupts remote spatial memories in mice. Learn Mem 15:1–5CrossRefPubMedGoogle Scholar
  47. 47.
    Yang Y, Chen X, Margulies K, Jeevanandam V, Pollack P, Bailey BA, Houser SR (2000) L-type Ca2+ channel alpha 1c subunit isoform switching in failing human ventricular myocardium. J Mol Cell Cardiol 32:973–984CrossRefPubMedGoogle Scholar
  48. 48.
    Yarotskyy V, Gao G, Peterson BZ, Elmslie KS (2009) The Timothy syndrome mutation of cardiac Cav1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation. J Physiol 587:551–565CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.National Neuroscience InstituteSingaporeSingapore
  2. 2.Department of Physiology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Personalised recommendations