Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices
- 28 February 2006
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 103 (10), 3932-3937
- https://doi.org/10.1073/pnas.0511322103
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 transplant patients.Keywords
This publication has 32 references indexed in Scilit:
- Role of Hippocampal Cav1.2 Ca2+Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial MemoryJournal of Neuroscience, 2005
- The channelopathies: novel insights into molecular and genetic mechanisms of human diseaseJCI Insight, 2005
- Calmodulin reverses rundown of L-type Ca2+ channels in guinea pig ventricular myocytesAmerican Journal of Physiology-Cell Physiology, 2004
- Mechanisms for Regulation of Calmodulin Kinase IIα by Ca2+/Calmodulin and Autophosphorylation of Threonine 286Biochemistry, 2002
- Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytesThe Journal of Physiology, 2002
- Signaling to the Nucleus by an L-type Calcium Channel-Calmodulin Complex Through the MAP Kinase PathwayScience, 2001
- Specificity and mechanism of action of some commonly used protein kinase inhibitorsBiochemical Journal, 2000
- The mechanism of action of cyclosporin A and FK506Immunology Today, 1992
- Enzymatic Gating of Voltage‐Activated Calcium ChannelsAnnals of the New York Academy of Sciences, 1991
- Mechanisms of calcium channel modulation by β-adrenergic agents and dihydropyridine calcium agonistsJournal of Molecular and Cellular Cardiology, 1986