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Review
. 2012 Mar 1;121(3):173-80.
doi: 10.1016/j.drugalcdep.2011.10.027. Epub 2011 Nov 29.

μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology

John Traynor  1
Affiliations
Review

μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: from a symposium on new concepts in mu-opioid pharmacology

John Traynor. Drug Alcohol Depend. .

Abstract

Mu-opioid receptors (MOR) are the therapeutic target for opiate analgesic drugs and also mediate many of the side-effects and addiction liability of these compounds. MOR is a seven-transmembrane domain receptor that couples to intracellular signaling molecules by activating heterotrimeric G proteins. However, the receptor and G protein do not function in isolation but their activities are moderated by several accessory and scaffolding proteins. One important group of accessory proteins is the regulator of G protein signaling (RGS) protein family, a large family of more than thirty members which bind to the activated Gα subunit of the heterotrimeric G protein and serve to accelerate signal termination. This action negatively modulates receptor signaling and subsequent behavior. Several members of this family, in particular RGS4 and RGS9-2 have been demonstrated to influence MOR signaling and morphine-induced behaviors, including reward. Moreover, this interaction is not unidirectional since morphine has been demonstrated to modulate expression levels of RGS proteins, especially RGS4 and RGS9-2, in a tissue and time dependent manner. In this article, I will discuss our work on the regulation of MOR signaling by RGS protein activity in cultured cell systems in the context of other in vitro and behavioral studies. In addition I will consider implications of the bi-directional interaction between MOR receptor activation and RGS protein activity and whether RGS proteins might provide a suitable and novel target for medications to manage addictive behaviors.

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Conflict of interest statement

Conflict of interest: This author has no conflict of interest.

Figures

Figure 1
Figure 1
Diagram of the G protein cycle. The seven-transmembrane domain MOR is associated with the Gαβγ heterotrimeric G protein with the Gα subunit bound to GDP. Activation of MOR by agonist promotes the exchange of GDP for GTP on the Gα subunit and separation of the Gα and βγ subunits which interact with downstream effectors. Active Gα-GTP is hydrolyzed by the GTPase activity of the Gα subunit to provide Gα-GDP which recombines with the βγ subunits thus terminating signaling. This process is accelerated by the GAP activity of the RGS protein binding to the GTP-bound Gα subunit.
Figure 2
Figure 2
MOR agonists have a higher potency and maximal inhibition of cAMP accumulation (a measure of adenylate cyclase activity) in cells expressing RGS-insensitive Gαo (RGSi-Gαo) than in cells expressing wild-type (w/t) Gαo. The effect is more pronounced for the partial agonist morphine. This research was originally published in the Journal of Biological Chemistry by Clark and colleagues; Endogenous RGS Protein Action Modulates μ-Opioid Signaling through Gαo: effects on adenylate cyclase, extracellular signal-regulated kinases, and intracellular calcium pathways (Clark et al., 2003). © The American Society for Biochemistry and Molecular Biology.
Figure 3
Figure 3
Schematic to indicate how MOR agonist-induced down-regulation of RGS4 protein which negatively modulates signaling to DOR and muscarinic M3 receptors, allows for increased signaling at these receptors, including exposure of an ability of M3 receptors to stimulate AC activity via increased Ca2+ release. This figure was originally published in the Journal of Biological Chemistry by Wang and Traynor; Opioid-Induced Down-Regulation of RGS4: Role of ubiquitination and Implications for receptor cross-talk (Wang and Traynor, 2009). © The American Society for Biochemistry and Molecular Biology.
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