Calmodulin is the Ca2+ sensor for Ca2+ -dependent inactivation of L-type calcium channels.
Elevated intracellular Ca2+ triggers inactivation of L-type calcium channels, providing negative Ca2+ feedback in many cells. Ca2+ binding to the main alpha1c channel subunit has been widely proposed to initiate such Ca2+ -dependent inactivation. Here, we find that overexpression of mutant, Ca2+ -insensitive calmodulin (CaM) ablates Ca2+ -dependent inactivation in a "dominant-negative" manner. This result demonstrates that CaM is the actual Ca2+ sensor for inactivation and suggests that CaM is constitutively tethered to the channel complex. Inactivation is likely to occur via Ca2+ -dependent interaction of tethered CaM with an IQ-like motif on the carboxyl tail of alpha1c. CaM also binds to analogous IQ regions of N-, P/Q-, and R-type calcium channels, suggesting that CaM-mediated effects may be widespread in the calcium channel family.
Peterson
B Z
BZ
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
DeMaria
C D
CD
Adelman
J P
JP
Yue
D T
DT
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020013:Calcium Signaling / Q000502:physiology*; D002147:Calmodulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D005246:Feedback / Q000502:physiology; D008564:Membrane Potentials; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D051381:Rats
D002118:Calcium; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D002147:Calmodulin