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.
Erxleben
Christian
C
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Liao
Yanhong
Y
Gentile
Saverio
S
Chin
David
D
Gomez-Alegria
Claudio
C
Mori
Yasuo
Y
Birnbaumer
Lutz
L
Armstrong
David L
DL
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