Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin
- Departments of *Anesthesiology, †Biological Chemistry, and ‡Molecular, Cell and Developmental Biology, and §Brain Research, and ¶Molecular Biology Institutes, University of California, Los Angeles, CA 90095-1778
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Contributed by Lutz Birnbaumer
Abstract
Ca2+-induced inhibition of α1C voltage-gated Ca2+ channels is a physiologically important regulatory mechanism that shortens the mean open time of these otherwise long-lasting high-voltage-activated channels. The mechanism of action of Ca2+ has been a matter of some controversy, as previous studies have proposed the involvement of a putative Ca2+-binding EF hand in the C terminus of α1C and/or a sequence downstream from this EF-hand motif containing a putative calmodulin (CaM)-binding IQ motif. Previously, using site directed mutagenesis, we have shown that disruption of the EF-hand motif does not remove Ca2+ inhibition. We now show that the IQ motif binds CaM and that disruption of this binding activity prevents Ca2+ inhibition. We propose that Ca2+ entering through the voltage-gated pore binds to CaM and that the Ca/CaM complex is the mediator of Ca2+ inhibition.
ABBREVIATIONS
- CaM,
- calmodulin;
- GSH,
- glutathione;
- GST,
- glutathione S-transferase
- Accepted December 31, 1998.
- Copyright © 1999, The National Academy of Sciences
