Selective regulation of N-type Ca channels by different combinations of G-protein beta/gamma subunits and RGS proteins

We examined the effects of G-protein beta and gamma subunit heterodimers on human alpha(1B) (N-type) Ca channels expressed in HEK293 cells. All of the known beta subunits (beta 1-beta 5) produced voltage-dependent inhibition of alpha(1B)Ca channels, depending on the gamma subunit found in the hetero dimer. beta 1-beta 4 subunits inhibited Ca channels when paired with gamma 1-gamma 3. However, beta 5 subunits only produced inhibition when paired wi th gamma 2. In contrast, heterodimers between beta 5 subunits and RGS (regu lators of G-protein signaling) proteins containing GGL domains did not prod uce inhibition of Ca channels. However, GGL domain-containing RGS proteins (e.g., RGS6 and RGS11) did block the ability of G beta 5/gamma 2 heterodime rs to inhibit Ca channels. Because all of the G-protein beta subunits are f ound in the nervous system, we conclude that they may all potentially parti cipate in Ca channel inhibition. The interaction of GGL-containing RGS prot eins with G beta 5 gamma 2 suggests a novel way in which Ca channels can be regulated.