Targeting regulators of G protein signaling (RGS proteins) to enhance agonist specificity

Summary

Members of the diverse regulator of G protein signaling (RGS protein) family enhance the GTPase activity of G protein alpha subunits and speed their deactivation. Thus they negatively regulate signal transduction mediated by Gi- and Gq-coupled receptors. RGS proteins exhibit both tonic and regulated inhibition of agonist responses, differentially controlling the sensitivity of tissues depending on their post-translational modifications and expression levels. Reducing the activity of RGS proteins genetically or by means of chemical inhibitors can enhance G protein coupled receptor (GPCR) responses. RGS inhibitors present the novel possibility of enhancing agonist selectivity in a manner that depends on the signaling pathway employed or the tissue in which the receptor resides. To fully exploit this capability, more information will be needed about the expression of RGS proteins in different tissues and under distinct pathophysiological circumstances. Also, advances in the development of cell-permeable high affinity and selective inhibitors of specific RGS proteins will be needed. Finally, animal models illustrating the physiological functions of RGS proteins will be essential to predicting the actions in humans.

G protein coupled receptors (GPCRs) play a major role in signal transduction and are the targets of many therapeutic drugs. Signaling by G proteins is initiated by the agonist-mediated exchange of GTP for GDP on the Gα subunit and signaling is terminated by the hydrolysis of GTP to GDP followed by reassociation of the Gα and βγ subunits (Ross and Wilkie 2000). A recently described protein family, the regulator of G protein signaling (RGS) proteins, enhances the deactivation of the activity of G proteins and has now been show to play a major role in the control of GPCR signaling in vivo. In this report, I describe the mechanism and role of RGS proteins in controlling GPCR signaling and the potential utility of RGS inhibitors to enhance GPCR agonist responses.

The best known function of RGS proteins is to inhibit G protein signaling by accelerating GTP hydrolysis, thus turning off G protein signals (Berman et al. 1996). They are a highly diverse protein family, have unique tissue distributions, and are strongly regulated by signal transduction events (Hollinger and Hepler 2002; Neubig and Siderovski 2002). Also, evidence is emerging that, besides causing G protein inhibition, they can maintain efficient G protein signaling, serve as effectors to control downstream signals, and act as scaffold proteins to gather receptors, G proteins, effectors, and other regulatory molecules together (Siderovski et al. 1999; Hepler 2003).