Kinetic Modeling of CaV3.1

Abstract

T-type calcium channel kinetics have been well characterized at the macroscopic level, but less well so at the single channel level. The most thorough single channel kinetic analyses have been performed using recordings from native tissues where the specific isoform(s) present is unknown. As a result there is some discrepancy as to magnitude and voltage dependence of fundamental descriptors such as mean open time. It has been reported to be 0.5-2.5ms and either weakly voltage dependent or voltage independent (summarized in Perez-Reyes 2003). Macroscopic current measurements, on the other hand, are consistent with a voltage dependent O->C transition, suggesting that mean open time is voltage dependent. Bandwidth differences and other issues associated with signal to noise ratio for these conductance channels have no doubt contributed to measured durations. The development of gating models for these channels has been hampered by the paucity of high quality single channel data. Furthermore, previously published gating models of CaV3.1 correctly approximate the voltage dependence and time course of the macroscopic currents of CaV3.1 but fail to appropriately recapitulate the gating currents (Serrano et al 1999, Burgess et al 2002). We have utilized low noise recording methods to obtain higher bandwidth single channel data and paired it with maximum idealized point-likelihood analysis in QuB to estimate rate constants and their voltage dependence from single channel data for inclusion in developing models that correctly recapitulate macroscopic, single channel, and gating current data. Supported by F31-NS058334 (K.B.) and RO1-HL065680 (D.H.)