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- Title
RGS14 regulates the lifetime of G α-GTP signaling but does not prolong G βγ signaling following receptor activation in live cells.
- Authors
Brown, Nicole E.; Lambert, Nevin A.; Hepler, John R.
- Abstract
RGS14 is a multifunctional scaffolding protein possessing two distinct G protein interaction sites including a regulator of G protein signaling (RGS) domain that acts as a GTPase activating protein (GAP) to deactivate G αi/o-GTP proteins, and a G protein regulatory (GPR) motif that binds inactive G αi1/3-GDP proteins independent of G βγ. GPR interactions with G αi recruit RGS14 to the plasma membrane to interact with G αi-linked GPCRs and regulate G αi signaling. While RGS14 actions on G α proteins are well characterized, consequent effects on G βγ signaling remain unknown. Conventional RGS proteins act as dedicated GAPs to deactivate G α and G βγ signaling following receptor activation. RGS14 may do the same or, alternatively, may coordinate its actions to deactivate G α-GTP with the RGS domain and then capture the same G α-GDP via its GPR motif to prevent heterotrimer reassociation and prolong G βγ signaling. To test this idea, we compared the regulation of G protein activation and deactivation kinetics by a conventional RGS protein, RGS4, and RGS14 in response to GPCR agonist/antagonist treatment utilizing bioluminescence resonance energy transfer (BRET). Co-expression of either RGS4 or RGS14 inhibited the release of free G βγ after agonist stimulation and increased the deactivation rate of G α, consistent with their roles as GTPase activating proteins (GAPs). Overexpression of inactive G αi1 to recruit RGS14 to the plasma membrane did not alter RGS14′s capacity to act as a GAP for a second G αo protein. These results demonstrate the role of RGS14 as a dedicated GAP and suggest that the G protein regulatory (GPR) motif functions independently of the RGS domain and is silent in regulating GAP activity in a cellular context.
- Subjects
GTPASE-activating protein; REGULATOR of G-protein-signaling proteins; LUCIFERASES; ADRENERGIC receptors; HEMAGGLUTININ
- Publication
Pharmacology Research & Perspectives, 2016, Vol 4, Issue 5, pn/a
- ISSN
2052-1707
- Publication type
Article
- DOI
10.1002/prp2.249