Physiology and Biophysics
August 5, 2015
Rose E. Dixon, PhD, University of Washington
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January 21, 2016 @ 9:30 am – 10:30 am
L-type Ca2+ Channel Oligomerization in Hearts and MindsIn ventricular myocytes, excitation-contraction (EC) coupling occurs via a Ca2+ induced Ca2+ release mechanism such that the depolarization created by an action potential (AP) triggers Ca2+ influx through voltage-dependent L-type Ca2+ channels (i.e., Cav1.2 channels), which in turn stimulates further Ca2+ release from ryanodine receptors (RyRs) on the nearby junctional sarcoplasmic reticulum. The simultaneous activation of multiple RyRs across the myocyte results in a cell-wide increase in intracellular Ca2+ and triggers contraction. This process is remarkably reproducible despite the confounding fact that, at the membrane potential reached during the AP plateau, the driving force for Ca2+ entry through a single Cav1.2 channel is not sufficient to reliably activate RyRs. Instead it has been proposed that up to ten Cav1.2 channels must open simultaneously during the AP plateau to achieve this coupling fidelity. The mechanism that permits coordinated opening of multiple Cav1.2 channels during EC-coupling, however, has not yet been elucidated. Using electrophysiological, and optical approaches, we have found that an allosteric interaction between the C-terminal domains of voltage-gated CaV1.2 channels induces an increase in the open probability of the channels that amplifies Ca2+ influx during the AP and contributes to reproducible EC-coupling. We have also discovered that Cav1.3 channels that regulate excitability in neurons often display the same cooperative behavior. The objectives of this presentation are to summarize the molecular details of the channel interactions that we have resolved thus far and to highlight the significance of these findings to the cardiac and neuronal field Rose Dixon, Ph.D. University of Washington Chalk talk, Friday, January 22nd, at 9:30 in G-417.