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

ABSTRACT: 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 (beta1-beta5) produced voltage-dependent inhibition of alpha(1B) Ca channels, depending on the gamma subunit found in the heterodimer. beta1-beta4 subunits inhibited Ca channels when paired with gamma1-gamma3. However, beta5 subunits only produced inhibition when paired with gamma2. In contrast, heterodimers between beta5 subunits and RGS (regulators of G-protein signaling) proteins containing GGL domains did not produce inhibition of Ca channels. However, GGL domain-containing RGS proteins (e.g., RGS6 and RGS11) did block the ability of Gbeta5/gamma2 heterodimers to inhibit Ca channels. Because all of the G-protein beta subunits are found in the nervous system, we conclude that they may all potentially participate in Ca channel inhibition. The interaction of GGL-containing RGS proteins with Gbeta5gamma2 suggests a novel way in which Ca channels can be regulated.

SUBMITTER: Zhou JY

PROVIDER: S-EPMC6772774 | biostudies-literature | 2000 Oct

REPOSITORIES: biostudies-literature

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

Zhou J Y JY Siderovski D P DP Miller R J RJ

The Journal of neuroscience : the official journal of the Society for Neuroscience 20001001 19

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 (beta1-beta5) produced voltage-dependent inhibition of alpha(1B) Ca channels, depending on the gamma subunit found in the heterodimer. beta1-beta4 subunits inhibited Ca channels when paired with gamma1-gamma3. However, beta5 subunits only produced inhibition when paired with gamma2. In contrast, heterodimers between beta5 subun ...[more]

PMID: 11007869

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Project description:The interactions between guanine nucleotide regulatory proteins and the Ca(2+)-binding protein calmodulin were studied using calmodulin-Sepharose affinity chromatography. Purified bovine brain beta gamma subunits bound to calmodulin-Sepharose in a Ca(2+)-dependent manner. On the contrary, beta gamma subunits produced in an activated Go/Gi preparation did not bind to calmodulin-Sepharose. The effect was independent of the type of bovine brain G protein (Go/Gi, Gs), method of activation and the presence of magnesium. To distinguish whether the binding of purified beta gamma subunits to calmodulin was unique to brain beta gamma or to the method of purification, similar experiments were performed using transducin. In contrast to bovine brain G proteins, both purified transducin beta gamma subunits and beta gamma released from rhodopsin-activated transducin bound to calmodulin-Sepharose in a Ca(2+)-dependent manner. To assess the functional significance of the binding of bovine brain beta gamma subunits to calmodulin, the ability of purified beta gamma and of beta gamma in unactivated and activated Go/Gi to inhibit partially purified calmodulin-sensitive adenylate cyclase was determined. Purified beta gamma was highly effective in inhibiting calmodulin-stimulated adenylate cyclase activity. However, unactivated Go/Gi and preactivated Go/Gi inhibited calmodulin-stimulated adenylate cyclase activity to the same extent. This Go/Gi-mediated inhibition also occurred in the presence of a 500-fold molar excess of calmodulin over added G protein. These results demonstrate: (1) that beta gamma subunits may not be completely released upon G protein activation, and (2) that inhibition of calmodulin-stimulated adenylate cyclase by beta gamma subunits does not appear to be mediated by a direct beta gamma-calmodulin interaction. Differences in the binding properties of activated bovine brain G proteins versus those of transducin could be explained by differences in the gamma subunit between the proteins, or by differences in affinities of the alpha and beta gamma subunits for each other and for calmodulin. The different functional properties of purified beta gamma subunits and beta gamma subunits produced in situ by activation of G proteins indicates that extrapolation from the effects of purified subunits to events occurring in membranes should be done with caution.

Dataset Information

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

Publications

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

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