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Author Notes:

Correspondence: John R. Hepler, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd, Rollins Research Center Suite G205, Atlanta, GA 30322. Tel: 404 727 3641; Fax: 404‐727‐0365; E‐mail: jhepler@emory.edu

Participated in research design: Brown, Lambert, Hepler.

Conducted experiments: Brown.

Contributed new reagents or analytic tools: Lambert.

Performed data analysis: Brown, Hepler.

Wrote or contributed to the writing of the manuscript: Brown, Lambert, Hepler.

We acknowledge Suneela Ramineni for technical advice in support of this project.

We also acknowledge Kyle Gerber and Katherine Squires for insightful discussions on RGS14 function.

Disclosures: None declared.


Research Funding:

National Institutes of Health. Grant Numbers: 5R01NS037112, 5R21NS074975, R01GM078319, R01GM109879

National Institutes of Health Pharmacological Sciences Predoctoral Research Training. Grant Number: T32M008602

American Heart Association Predoctoral. Grant Number: 14PRE18850017


  • G protein
  • GPCR
  • Gαi1
  • Gβγ
  • RGS protein
  • RGS14.

RGS14 regulates the lifetime of Gα-GTP signaling but does not prolong Gβγ signaling following receptor activation in live cells.


Journal Title:

Pharmacology Research and Perspectives


Volume 4, Number 5


, Pages e00249-e00249

Type of Work:

Article | Final Publisher PDF


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 Gαi/o-GTP proteins, and a G protein regulatory (GPR) motif that binds inactive Gαi1/3-GDP proteins independent of Gβγ. GPR interactions with Gαi recruit RGS14 to the plasma membrane to interact with Gαi-linked GPCRs and regulate Gαi signaling. While RGS14 actions on Gα proteins are well characterized, consequent effects on Gβγ signaling remain unknown. Conventional RGS proteins act as dedicated GAPs to deactivate Gα and Gβγ signaling following receptor activation. RGS14 may do the same or, alternatively, may coordinate its actions to deactivate Gα-GTP with the RGS domain and then capture the same Gα-GDP via its GPR motif to prevent heterotrimer reassociation and prolong Gβγ 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 Gβγ after agonist stimulation and increased the deactivation rate of Gα, consistent with their roles as GTPase activating proteins (GAPs). Overexpression of inactive Gαi1 to recruit RGS14 to the plasma membrane did not alter RGS14's capacity to act as a GAP for a second Gαo 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.

Copyright information:

© 2016 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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