Key result
Mutant CaM overexpression ablates Ca2+-dependent L-type calcium channel inactivation, demonstrating CaM is the actual Ca2+ sensor.
Demonstrates that calmodulin is the actual Ca2+ sensor for Ca2+-dependent inactivation of L-type calcium channels, interacting with an IQ-like motif on the alpha1c subunit.
Provides foundational insight into Ca2+ channel gating; leaves open whether CaM modulation offers cardiovascular therapeutic targets.
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.
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Peterson et al. (1999) studied L-type calcium channel inactivation. Overexpression of mutant, Ca2+-insensitive calmodulin (CaM) was evaluated on Ca2+-dependent inactivation of L-type calcium channels. Overexpression of mutant, Ca2+-insensitive calmodulin ablated Ca2+-dependent inactivation of L-type calcium channels, demonstrating that CaM is the actual Ca2+ sensor for inactivation.
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