Biochemistry 2012 Dec 04;5148:9658-66. doi: 10.1021/bi301124a.

Voltage-driven Ca(2+) binding at the L-type Ca(2+) channel triggers cardiac excitation-contraction coupling prior to Ca(2+) influx.

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The activation of the ryanodine Ca(2+) release channels (RyR2) by the entry of Ca(2+) through the L-type Ca(2+) channels (Cav1.2) is believed to be the primary mechanism of excitation-contraction (EC) coupling in cardiac cells. This proposed mechanism of Ca(2+)-induced Ca(2+) release (CICR) cannot fully account for the lack of a termination signal for this positive feedback process. Using Cav1.2 channel mutants, we demonstrate that the Ca(2+)-impermeable α(1)1.2/L775P/T1066Y mutant introduced through lentiviral infection into neonate cardiomyocytes triggers Ca(2+) transients in a manner independent of Ca(2+) influx. In contrast, the α(1)1.2/L775P/T1066Y/4A mutant, in which the Ca(2+)-binding site of the channel was destroyed, supports neither the spontaneous nor the electrically evoked contractions. Ca(2+) bound at the channel selectivity filter appears to initiate a signal that is conveyed directly from the channel pore to RyR2, triggering contraction of cardiomyocytes prior to Ca(2+) influx. Thus, RyR2 is activated in response to a conformational change in the L-type channel during membrane depolarization and not through interaction with Ca(2+) ions diffusing in the junctional gap space. Accordingly, termination of the RyR2 activity is achieved when the signal stops upon the return of the L-channel to the resting state. We propose a new model in which the physical link between Cav1.2 and RyR2 allows propagation of a conformational change induced at the open pore of the channel to directly activate RyR2. These results highlight Cav1.2 as a signaling protein and provide a mechanism for terminating the release of Ca(2+) from RyR2 through protein-protein interactions. In this model, the L-type channel is a master regulator of both initiation and termination of EC coupling in neonate cardiomyocytes.

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Species referenced: Xenopus
Genes referenced: cacna1c cav1