Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling

Abstract

Regulators of G protein signaling (RGS) and RGS-like proteins are a family (>30 members) of highly diverse, multifunctional signaling proteins that bind directly to activated G alpha subunits. Family members are defined by a shared RGS domain, which is responsible for G alpha binding and markedly stimulates the GTPase activity of G alpha subunits leading to their deactivation and termination of downstream signals. Although much has been learned in recent years about the biochemistry of RGS/G alpha interactions, considerably less is known about the broader cellular roles and regulation of RGS proteins. Recent findings indicate that cellular mechanisms such as covalent modification, alternative gene splicing, and protein processing can dictate the activity and subcellular localization of RGS proteins. Many family members also directly link G proteins to a growing list of signaling proteins with diverse cellular roles. New findings indicate that RGS proteins act not as dedicated inhibitors but, rather, as tightly regulated modulators and integrators of G protein signaling. In some cases, RGS proteins modulate the lifetime and kinetics of both slow-acting (e.g., Ca(2+) oscillations) and fast-acting (e.g., ion conductances, phototransduction) signaling responses. In other cases, RGS proteins integrate G proteins with signaling pathways linked to such diverse cellular responses as cell growth and differentiation, cell motility, and intracellular trafficking. These and other recent studies with animal model systems indicate that RGS proteins play important roles in both physiology and disease. Recognition of the central functions these proteins play in vital cellular processes has focused our attention on RGS proteins as exciting new candidates for therapeutic intervention and drug development.

Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

“…The regulator of G-protein signaling 1, known as RGS1, is involved in the trafficking of Treg and other immune cells by restricting G-protein signaling duration (Hollinger et al, 2002). Although RGS1 variants were associated with autoimmune diseases as arthritis and psoriasis (Hunt et a., 2008), an alteration of its gene expression was not observed in this work.…”

“…Interestingly, all these genes are involved in the immune system regulation with predominant antiinflammatory role and in the development of autoimmune diseases (Hollinger et al, 2002;Yao et al 2009;Sanduja et al, 2011;Roychoudhuri et al, 2013;Hunt et al, 2008;Medici et al, 2014;Perdigones et al, 2010;Grant et al, 2009). …”

“…This approach highlighted 5 matching genes namely as tumor necrosis factor alpha-induced protein 3 (TNFAIP3), BTB and CNC Homology 1 basic leucine zipper transcription factor 2 (BACH2), prostaglandin E receptor 4 (Subtype EP4) (PTGER4), regulator of G-protein signaling 1 (RGS1), and zinc finger protein 36-C3H-type-like 1 (ZFP36L1). Interestingly, all these transcripts were previously reported as involved in the immune system regulation, mainly with an anti-inflammatory role (Hollinger et al, 2002;Murn et al, 2008;Yao et al 2009;Esaki et al, 2010;Sanduja et al, 2011;Roychoudhuri et al, 2013) and associated to several autoimmune diseases (Hunt et al, 2008;Medici et al, 2014;Perdigones et al, 2010;Grant et al, 2009). …”

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

“…This receptor can modulate cocaine-induced behaviors (Matsumoto et al, 2002;Romieu et al, 2003). RGS proteins are a family of diverse and multifunctional signaling proteins that modulate G-protein functions (Zhong and Neubig, 2001;Hollinger and Hepler, 2002). RGS4 is exclusively expressed in the brain (Zhong and Neubig, 2001;Hollinger and Hepler, 2002).…”

RGSZ1 and GAIP Regulate μ- but Not δ-Opioid Receptors in Mouse CNS: Role in Tachyphylaxis and Acute Tolerance

“…All are similarly organized. The regions flanking the RGS domain all contain a DEP domain (dishevelled, EGL-10, pleckstrin), the R7 homology domain (R7H), and the Gprotein (heterotrimeric guanine nucleotide-binding regulatory protein) g subunit-like (GGL) domain that binds to the Gb5 protein but not to other Gb subunits (for a review, see Hollinger and Hepler, 2002). Members of the R12 subfamily show notable differences in size and the domains flanking the RGS box.…”