Function of Regulator of G Protein Signaling (RGS) Proteins in the Heart

Regulator of G protein signaling (RGS) proteins terminate G protein signaling by enhancing the rate of GTP hydrolysis by the Gα subunit of G proteins.  More than 20 different RGS proteins have been identified.  Transcripts encoding most of them are present in the heart, but it is unclear how many different RGS proteins are expressed in the heart at the protein level.  RGS proteins differ with respect to their tissue distribution and the specific G proteins that they interact with.  This makes them attractive targets for the development of new therapeutic drugs.

Our laboratory used a transgenic mouse model (developed by Richard Neubig) that expresses a form of Gαi2 that does not interact with RGS proteins.  This model provides a tool to explore the impact of disrupting interactions between RGS proteins and Gαi2. This enhances signaling through Gαi2.  Gαi- coupled receptors have a well established role in cardioprotection.  We found that disrupting the interaction between RGS proteins and Gαi2 protects the heart from ischemic injury, suggesting that RGS proteins might provide a novel therapeutic target to protect the heart from myocardial ischemia.

We have used a variety of RGS knockout mouse lines to investigate the ability of specific RGS proteins to modulate the myocardial response to ischemic injury. Our work demonstrated that RGS6 protects the heart from ischemic injury.

Relevant Publications:

Rorabaugh BR, Chakravarti B, Mabe NW, Seeley SL, Bui AD, Yang J, Watts SW, Neubig RR, Fisher RA (2017). Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury. Journal of Pharmacology and Experimental Therapeutics 360:409-416.

Parra S, Huang X, Charbeneau R, Wade S, Kaur K, Rorabaugh BR, Neubig RR (2014) Conditional disruption of interactions between Gαi2 and regulator of G protein signaling (RGS) proteins protects the heart from ischemic injury. BMC Pharmacology and Toxicology 15:29

Waterson R, Thompson C, Mabe N, Kaur K, Talbot JN, Neubig RR, Rorabaugh BR  (2011) Gαi2-mediated protection from ischemic injury is modulated by endogenous RGS proteins in the mouse heart. Cardiovascular Research 91:45-52.