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Voltage-Driven Ca<sup>2+</sup> Binding at the L‑Type Ca<sup>2+</sup> Channel Triggers Cardiac Excitation–Contraction Coupling Prior to Ca<sup>2+</sup> Influx

By Liron S. Gez (2017411), Yamit Hagalili (2017414), Asher Shainberg (446427) and Daphne Atlas (36965)


The activation of the ryanodine Ca<sup>2+</sup> release channels (RyR2) by the entry of Ca<sup>2+</sup> through the L-type Ca<sup>2+</sup> channels (Cav1.2) is believed to be the primary mechanism of excitation–contraction (EC) coupling in cardiac cells. This proposed mechanism of Ca<sup>2+</sup>-induced Ca<sup>2+</sup> 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<sup>2+</sup>-impermeable α<sub>1</sub>1.2/L775P/T1066Y mutant introduced through lentiviral infection into neonate cardiomyocytes triggers Ca<sup>2+</sup> transients in a manner independent of Ca<sup>2+</sup> influx. In contrast, the α<sub>1</sub>1.2/L775P/T1066Y/4A mutant, in which the Ca<sup>2+</sup>-binding site of the channel was destroyed, supports neither the spontaneous nor the electrically evoked contractions. Ca<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> 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

Topics: Biophysics, Biochemistry, Cell Biology, Molecular Biology, Neuroscience, Physiology, Infectious Diseases, Cav 1.2 channel mutants, 775P, EC, junctional gap space, channel selectivity filter, Cav 1.2, CICR, RyR 2 activity, RyR 2, neonate cardiomyocytes triggers
Year: 2012
DOI identifier: 10.1021/bi301124a.s001
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Provided by: FigShare
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