Elevated intracellular Ca2+ triggers inactivation of L-type calcium channels, providing negative Ca2+ feedback in many cells. Ca2+ binding to the main α(1C) 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 α(1C). 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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