Evidence for Common Structural Determinants of Activation and Inactivation in T-type Ca2+ Channels

One of the most distinctive features of T-type Ca(2+) channels is their fast inactivation. Recent structure-function studies indicate that the rate of macroscopic inactivation of these channels is influenced by several structural components, including intracellular linkers, transmembrane segments, and pore loops. The macroscopic inactivation of T-type channels is partially coupled to activation. It is therefore possible that changes in the rate of macroscopic inactivation after alteration in the structure of these channels might actually result from changes in activation kinetics. In this study, we use kinetic simulations to illustrate how the alteration of the rate of channel activation may lead to changes in the rate of macroscopic inactivation. By examining data pooled from several structure-function studies we demonstrate that gating modifications induced by alteration in the channel structure unveils a correlation between the time constants of macroscopic inactivation and activation. This analysis underscores the relevance of considering the inactivation-activation coupling when analyzing the structural determinants of T-type channel inactivation. Furthermore, we demonstrate that slow-inactivating mutants, with modifications in the IIIS6 segment and the proximal C terminus, display significant alterations in the voltage dependencies of activation and deactivation with respect to the wild type channel Ca(V)3.1. Our results indicate that common structures, most likely the S6 transmembrane segments, are involved in the conformational changes occurring during both channel activation and inactivation.