Ca2+ channel inactivation heterogeneity reveals physiological unbinding ofauxiliary beta subunits

Voltage gated Ca2+ channel (VGCC) auxiliary beta subunits increase membrane expression of the main pore-forming alpha (1) subunits and finely tune cha nnel activation and inactivation properties. In expression studies, co-expr ession of beta subunits also reduced neuronal Ca2+ channel regulation by he terotrimeric G protein. Biochemical studies suggest that VGCC beta subunits and G protein beta gamma can compete for overlapping interaction sites on VGCC alpha (1) subunits, suggesting a dynamic association of these subunits with alpha (1). In this work we have analyzed the stability of the alpha ( 1)/beta association under physiological conditions. Regulation of the alpha (1A) Ca2+ channel inactivation properties by beta (1b) and beta (2a) subun its had two major effects: a shift in voltage-dependent inactivation (E-in) , and an increase of the non-inactivating current (R-in). Unexpectedly, lar ge variations in magnitude of the effects were recorded on E-in, when beta (1b) was expressed, and R-in, when beta (2a) was expressed. These variation s were not proportional to the current amplitude, and occurred at similar l evels of beta subunit expression. beta (2a)-induced variations of R-in were , however, inversely proportional to the magnitude of G protein block. Thes e data underline the two different mechanisms used by beta (1b) and beta (2 a) to regulate channel inactivation, and suggest that the VGCC beta subunit can unbind the oil subunit in physiological situations.