Thermodynamic Linkage with Voltage Sensing Explains the Large Variability of Inactivation in L-Type Ca Channels with γ1 Subunit

Abstract

The voltage-dependence of steady-state inactivation (a.k.a. the inactivation curve) is an important determinant of functional availability of calcium channels. Some experimental and pathological conditions change the half-inactivation voltage (V1/2) but not the slope of the inactivation curve. We observed that the V1/2 varies from cell to cell by as much as 40 mV when CaV1.2 channels are co-expressed with γ1 subunit in tsA-201 cells. This parallel shift cannot be explained by a simple mixing of channels with different V1/2 values (e.g., with and without the γ1). We found that the γ1 subunit had a relatively small effect on inactivation assessed at the level of gating currents. It caused the voltage-dependence of the intramembrane charge movement in inactivated channels to shift by about −10 mV, and this effect did not vary from cell to cell. Therefore, the large shift of the inactivation curve seen at the level of ionic currents appears to be unrelated to the small changes observed at the level of the voltage sensor for activation/inactivation gating. We explain this paradox in the framework of a minimal four-state model of inactivation, in which the V1/2 parameter of the inactivation curve is determined by both the voltage-dependence of gating currents and the maximal extent (efficacy) of inactivation. The parallel shift of the inactivation curve may result solely from a change in the efficacy. Therefore, we propose that functional availability of CaV1.2 channels with the γ1 subunit is controlled by a cell-specific molecular modification that affects similarly all channels in a particular cell. This modification primarily alters the efficacy of inactivation and, thus, leads to large changes of the availability of channels to activate. Supported by NIH R01MH079406.