The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Abstract

Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

“…For example, we identified existing compounds as being potent inhibitors for RGS1, RGS10, RGS14, and RGS18, which have not been the subject of significant screening efforts. For these newly-revealed RGS-inhibitor pairs, each of the RGS proteins has been implicated in disease states, providing the rationale for continued development of these compounds (113,114). This study also highlights the polypharmacology that some RGS inhibitors may exhibit and provides a testbed for selectivity measurements for optimization of compounds through medicinal chemistry efforts.…”

“…The difficulty with developing selective small-molecule inhibitors of RGS proteins is attributed in large part to their RH domain. Not only is this RH domain shared (but not identical) by the entire RGS family, it is also found in a number of other protein families: for example the GRK family (114,115). Targeting the RH domain is therefore likely to result in the discovery of molecules that may not be completely selective.…”

RGS 9‐2 rescues dopamine D2 receptor levels and signaling in DYT 1 dystonia mouse models

“…With such premises, b-Arr2 and RGS9-2, as well as DRD2-biased drugs, have been proposed as drug targets (Traynor et al, 2009;Peterson & Luttrell, 2017;Urs et al, 2015;Sjögren, 2017). Accordingly, RGS9 has now been added to the IUPHAR/BPS Guide to Pharmacology database of drug targets.…”

Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

“…1). Furthermore, we have come to appreciate that regulation of G protein signaling is crucial for normal cellular function, and improperly regulated G protein signaling underlies many disease states (Gerber et al, 2016;Sjögren, 2017), signifying the potential for RGS proteins as therapeutic targets. In this review, we limit and focus our discussion to the 20 canonical RGS proteins.…”

“…Given this context, in this work we describe a genomics approach to identify likely deleterious rare human variants (defined in this study as less than 2% prevalence) in functionally sensitive regions of RGS proteins, with an emphasis on the well-defined RGS domain. Due to the likely involvement of RGS proteins in complex disease states (Sjögren, 2017), these variants may contribute to a first hit, leaving the carrier more vulnerable to disease given a secondary insult (e.g., environmental, subsequent mutation of a protein in related signaling pathway, or otherwise). Furthermore, both a loss-of-function (LoF) as well as a gain-offunction (GoF) variant could equally disrupt cellular systems in delicate equilibrium.…”