Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Proceedings of the National Academy of Sciences of the United States of America
Christian ErxlebenDavid L Armstrong

Abstract

Calcium channels in the plasma membrane rarely remain open for much more than a millisecond at any one time, which avoids raising intracellular calcium to toxic levels. However, the dihydropyridine-sensitive calcium channels of the CaV1 family, which selectively couple electrical excitation to endocrine secretion, cardiovascular contractility, and neuronal transcription, have a unique second mode of gating, "mode 2," that involves frequent openings of much longer duration. Here we report that two human conditions, cyclosporin neurotoxicity and Timothy syndrome, increase mode 2 gating of the recombinant rabbit CaV1.2 channel. In each case, mode 2 gating depends on a Ser residue at the cytoplasmic end of the S6 helix in domain I (Ser-439, Timothy syndrome) or domain IV (Ser-1517, cyclosporin). Both Ser reside in consensus sequences for type II calmodulin-dependent protein kinase. Pharmacologically inhibiting type II calmodulin-dependent protein kinase or mutating the Ser residues to Ala prevents the increase in mode 2 gating. We propose that aberrant phosphorylation, or "phosphorylopathy," of the CaV1.2 channel protein contributes to the excitotoxicity associated with Timothy syndrome and with chronic cyclosporin treatment of tra...Continue Reading

References

Apr 1, 1992·Immunology Today·S L Schreiber, G R Crabtree
Jan 1, 1991·Annals of the New York Academy of Sciences·D L ArmstrongR E White
Jul 1, 1986·Journal of Molecular and Cellular Cardiology·R W TsienM C Nowycky
Sep 1, 1986·The Journal of Physiology·J E Chad, R Eckert
Aug 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·S Kokubun, H Reuter
Dec 18, 1998·The Journal of Biological Chemistry·M WakamoriK Imoto
Jun 8, 2000·Current Topics in Cellular Regulation·J AramburuC B Klee
Jul 8, 2000·Trends in Cell Biology·D Chin, A R Means
Sep 22, 2000·The Biochemical Journal·S P DaviesP Cohen
Oct 14, 2000·Annual Review of Cell and Developmental Biology·W A Catterall
Oct 3, 2002·The Journal of Physiology·L F SantanaR Greven
Feb 26, 2003·Proceedings of the National Academy of Sciences of the United States of America·Christian ErxlebenDavid L Armstrong
Apr 17, 2004·Molecular Interventions·Natalie J SerkovaLeslie Z Benet
Jun 5, 2004·Trends in Cardiovascular Medicine·Mark E Anderson
Oct 1, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Leslie C Griffith
Oct 1, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Roger J Colbran
Nov 5, 2004·American Journal of Physiology. Cell Physiology·Jian-Jun XuMasaki Kameyama
Aug 3, 2005·The Journal of Clinical Investigation·Robert S Kass
Sep 1, 2005·The Journal of General Physiology·Cheng XieJian Yang
Oct 28, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sven MoosmangThomas Kleppisch

❮ Previous
Next ❯

Citations

Nov 17, 2009·Pflügers Archiv : European journal of physiology·Ping Liao, Tuck Wah Soong
Feb 6, 2008·Proceedings of the National Academy of Sciences of the United States of America·Curtis F Barrett, Richard W Tsien
Sep 16, 2008·Proceedings of the National Academy of Sciences of the United States of America·Saverio GentileDavid L Armstrong
May 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Anne BlaichSven Moosmang
Sep 16, 2010·The Journal of Biological Chemistry·Bin SongMingtao Li
Jan 11, 2011·The Journal of Biological Chemistry·Michael J Shipston
Dec 10, 2009·Molecular & Cellular Proteomics : MCP·Jian RenXuebiao Yao
Feb 10, 2010·The Journal of General Physiology·Michael R TadrossDavid T Yue
Aug 18, 2012·Antioxidants & Redox Signaling·Nitin T Aggarwal, Jonathan C Makielski
Jul 12, 2008·Annual Review of Cell and Developmental Biology·Sonia Cohen, Michael E Greenberg
Nov 10, 2009·American Journal of Physiology. Heart and Circulatory Physiology·Jabe M Best, Timothy J Kamp
Apr 4, 2009·Physiological Reviews·Shuiping DaiJohannes W Hell
Jan 30, 2010·Circulation Research·Manuel F NavedoLuis F Santana
Nov 13, 2008·Circulation·William H ThielMark E Anderson
Feb 3, 2012·Environmental Health Perspectives·Angela Spivey
Nov 2, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Seth F OliveriaWilliam A Sather
Nov 13, 2013·Journal of Molecular and Cellular Cardiology·Benjamin M L DrumLuis F Santana
Jan 31, 2015·Journal of Molecular and Cellular Cardiology·Konstantin WemhönerNiels Decher
Sep 25, 2012·Trends in Cardiovascular Medicine·Rose E DixonLuis F Santana
Apr 23, 2011·Revista española de cardiología·Leif Hove-Madsen
Jul 27, 2010·Journal of Molecular and Cellular Cardiology·Yasmin L HashambhoyRaimond L Winslow
Aug 8, 2009·Journal of Molecular and Cellular Cardiology·Jean-Pierre BenitahAna María Gómez
Sep 12, 2009·Pharmacology & Therapeutics·Peng Duan, Guofeng You
Apr 3, 2009·Current Opinion in Structural Biology·Arjun Narayanan, Matthew P Jacobson
Feb 13, 2008·Journal of Neurochemistry·Irina Calin-Jageman, Amy Lee
Jun 24, 2011·BioFactors·Stuart M Cain, Terrance P Snutch
Aug 10, 2015·Molecular and Cellular Neurosciences·Johanna G PasekRoger J Colbran
Aug 12, 2006·Journal of Molecular and Cellular Cardiology·Geoffrey S PittPenelope A Boyden
Dec 2, 2006·Cardiovascular Research·Geoffrey S Pitt
Dec 12, 2012·Journal of Molecular and Cellular Cardiology·Manuel F Navedo, Luis F Santana
Dec 12, 2012·Biochimica Et Biophysica Acta·Thomas Stockner, Alexandra Koschak
Feb 28, 2015·Journal of Molecular Cell Biology·Yongbo WangYu Xue
Apr 8, 2010·Biophysical Journal·Xianming WangBlaise Z Peterson
Jul 6, 2014·Frontiers in Pharmacology·Kevin P VincentAndrew G Edwards
Jul 6, 2014·Frontiers in Pharmacology·Donald M Bers, Stefano Morotti
Nov 16, 2016·International Journal of Molecular Sciences·Shoukai LinHuaqin He

❮ Previous
Next ❯

Related Concepts

Related Feeds

Caveolins & Signal Transduction

Caveolins are small proteins with a hairpin loop conformation that are located in the plasma membrane of various cell types where they bind cholesterol and interact with receptors essential for several signal transduction pathways. Here is the latest research.