Isoform-specific modulation of voltage-gated Na(+) channels by calmodulin.
Calmodulin (CaM) is a calcium-sensing protein that binds to Na(+) channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (micro1) but not cardiac (hH1) Na(+) channels. Mutant CaM(1234) did not alter the voltage dependence or the kinetics of gating of either micro1 or hH1. Mutation of the highly conserved IQ motif in the carboxyl terminus of both isoforms (IQ/AA) slowed the kinetics of current decay and abolished the effect of wild-type CaM on micro1, but did not alter hH1 currents. The IQ/AA mutation eliminated CaM binding to the carboxyl terminus of both micro1 and hH1 channels. Inhibition of Ca(2+)/CaM kinase (CaM-K) slowed the current decay, the rate of entry into inactivation, and shifted the voltage dependence of hH1 in the depolarizing direction independent of CaM overexpression with no effect on micro1 Na(+) channels. CaM signaling modulates Na(+) currents in an isoform-specific manner, via direct interaction with skeletal muscle Na(+) channels and through CaM-K in the case of the cardiac isoform. The full text of this article is available at http://www.circresaha.org.
Deschênes
Isabelle
I
Department of Medicine, Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, MD 21205, USA.
Neyroud
Nathalie
N
DiSilvestre
Deborah
D
Marbán
Eduardo
E
Yue
David T
DT
Tomaselli
Gordon F
GF
D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D002147:Calmodulin; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D015222:Sodium Channels; D012964:Sodium; D017871:Calcium-Calmodulin-Dependent Protein Kinases