August 5, 2015

Rose E. Dixon, PhD, University of Washington

L-type Ca²⁺ Channel Oligomerization in Hearts and Minds

In 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., Ca_v1.2 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 Ca_v1.2 channel is not sufficient to reliably activate RyRs. Instead it has been proposed that up to ten Ca_v1.2 channels must open simultaneously during the AP plateau to achieve this coupling fidelity. The mechanism that permits coordinated opening of multiple Ca_v1.2 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 Ca_V1.2 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 Ca_v1.3 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.