DIRECT BINDING OF G-PROTEIN BETA-GAMMA COMPLEX TO VOLTAGE-DEPENDENT CALCIUM CHANNELS

Voltage-dependent Ca2+ channels play a central role in controlling neu rotransmitter release at the synapse(1,2). They can be inhibited by ce rtain G-protein-coupled receptors, acting by a pathway intrinsic to th e membrane(3-6). Here we show that this inhibition results from a dire ct interaction between the G-protein beta gamma complex and the pore-f orming alpha(1) subunits of several types of these channels(7). The in teraction is mediated by the cytoplasmic linker connecting the first a nd second transmembrane repeats. Within this linker, binding occurs bo th in the alpha(1) interaction domain (AID)(8), which also mediates th e interaction between the alpha(1) and beta subunits of tbe channel, a nd in a second downstream sequence. Further analysis of the binding si te showed that several amino-terminal residues in the AID are critical for G beta gamma binding, defining a site distinct from the carboxy-t erminal residues shown to be essential for binding the beta-subunit of the Ca2+ channel(9). Mutation of an arginine residue within the N-ter minal motif abolished beta gamma binding and rendered the channel refr actory to G-protein modulation when expressed in Xenopus oocytes, show ing that the interaction is indeed responsible for G-protein-dependent modulation of Ca2+ channel activity.