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Review
. 2013;19(42):7333-47.
doi: 10.2174/138161281942140105160625.

Opioid receptor interacting proteins and the control of opioid signaling

Jennifer T Lamberts, John R Traynor  1
Affiliations
Review

Opioid receptor interacting proteins and the control of opioid signaling

Jennifer T Lamberts et al. Curr Pharm Des. 2013.

Abstract

Opioid receptors are seven-transmembrane domain receptors that couple to intracellular signaling molecules by activating heterotrimeric G proteins. However, the receptor and G protein do not function in isolation but their activities are modulated by several accessory and scaffolding proteins. Examples include arrestins, kinases, and regulators of G protein signaling proteins. Accessory proteins contribute to the observed potency and efficacy of agonists, but also to the direction of signaling and the phenomenon of biased agonism. This review will present current knowledge of such proteins and how they may provide targets for future drug design.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

Figures

Fig. (1).
Fig. (1).
Schematic illustration of the basic processes involved in opioid receptor signaling and regulation. Depicted are the canonical functions performed by (a) regulator of G protein signaling (RGS) proteins, (b) the kinases G protein-coupled receptor kinases (GRKs) and protein kinase C (PKC), and (c) arrestins. Agonist stimulation of μ, δ, and κ opioid receptors (1) results in the activation of associated heterotrimeric Gi/o proteins via nucleotide exchange (2). Once activated, Gαi/o-GTP dissociates from the βγ heterodimer, and both subunits signal to downstream effectors (3), including adenylate cyclase (AC), Ca2+ channels (Ca2+), G protein-coupled inwardly-rectifying K+ channels (GIRK), mitogen-activated protein kinases (MAPKs), and phospholipase C (PLC). G protein signaling is terminated by GTP hydrolysis, which is enhanced by RGS proteins (4). Agonist activation of opioid receptors also leads to desensitization, which is initiated by receptor phosphorylation by kinases such as GRKs and PKC (5). Arrestin proteins are then recruited to phosphorylated receptors (6), and this elicits further regulatory events, including receptor internalization, downregulation, and/or recycling (7). In addition, arrestin-bound opioid receptors have the ability to signal to MAPKs (8).
Fig. (2).
Fig. (2).
Diagram of the basic domain structures for “classical” regulator of G protein signaling (RGS) proteins of the R4, RZ, R7 and R12 families. Shown for each family is the common domain structure with the N-terminus oriented to the left, as well as a list of individual family members. The R4 and RZ families contain relatively simple RGS proteins, with short N- and C-terminal extensions. R4 family members, including RGS4, contain the RGS homology (RH) domain, together with a short N-terminal amphipathic helix. The RZ family is comprised of proteins with an N-terminal cysteine string preceding the conserved RH domain. The R7 and R12 families are more complex, and contain several domains for protein-protein interaction in addition to the RH domain. Members of the R7 family, including RGS9, contain both a DEP (Disheveled, Egl-10, Pleckstrin) domain with a helical extension (DHEX) and a GGL (G protein gamma-like) domain. The R12 family contains a PDZ (PSD95, Dlg1, ZO-1) domain, a phosphotyrosine binding (PTB) domain, Ras binding domains (RBD), and a GoLoco motif that binds Gα-GDP subunits. Highlighted in bold are the two primary RGS proteins discussed in this review.
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