Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices.
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.
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Christian
C
Erxleben
Yanhong
Y
Liao
Saverio
S
Gentile
David
D
Chin
Claudio
C
Gomez-Alegria
Yasuo
Y
Mori
Lutz
L
Birnbaumer
David L
DL
Armstrong
D019943:Amino Acid Substitution; D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008664:Metal Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D017354:Point Mutation; D011487:Protein Conformation; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013577:Syndrome
D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D011994:Recombinant Proteins; D016572:Cyclosporine