Ca(2+)-induced inhibition of the cardiac Ca(2+) channel depends on calmodulin

Ca(2+)-induced inhibition of α(1C) voltage-gated Ca(2+) 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 Ca(2+) has been a matter of some controversy, as previous studies have proposed the involvement of a putative Ca(2+)-binding EF hand in the C terminus of α(1C) 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 Ca(2+) inhibition. We now show that the IQ motif binds CaM and that disruption of this binding activity prevents Ca(2+) inhibition. We propose that Ca(2+) entering through the voltage-gated pore binds to CaM and that the Ca/CaM complex is the mediator of Ca(2+) inhibition.