MULTIPLE STRUCTURAL ELEMENTS IN VOLTAGE-DEPENDENT CA2-PROTEINS( CHANNELS SUPPORT THEIR INHIBITION BY G)

Molecular determinants of Ca2+ channel responsiveness to inhibition by receptor-coupled G proteins were investigated in Xenopus oocytes. The inhibitory response of alpha(1B) (N-type) channels was much larger th an alpha(1A) (P/Q-type) channels, while alpha(1C) (L-type) channels we re unresponsive. Differences in both degree and speed of inhibition we re accounted for by variations in inhibitor off-rate. We tested propos als that inhibitory G protein and Ca2+ channel beta subunits compete s pecifically at the I-II loop. G protein-mediated inhibition remained u naltered in alpha(1B) subunits containing a point mutation in the I-II loop segment critical for Ca2+ channel beta subunit binding, and in c himeras where the I-II loop of alpha(1B) was replaced with counterpart s from alpha(1A) or alpha(1C) Full interconversion between modulatory behaviors of alpha(1B) and alpha(1A) was achieved only by swapping bot h motif I and the C-terminus in combination. Thus, essential structura l elements for G protein modulation reside in multiple Ca2+ channel do mains.