Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin.
Ca2+-induced inhibition of alpha1C 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 alpha1C 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.
Department of Anesthesiology, University of California, Los Angeles, CA 90095-1778, USA.
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Qin
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Olcese
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Bransby
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Lin
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Birnbaumer
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006321:Heart / Q000502:physiology*; D008564:Membrane Potentials; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000502:physiology; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis
D015220:Calcium Channels; D002147:Calmodulin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D005982:Glutathione Transferase; D002118:Calcium