The Other Side of Opioid Receptor Signalling: Regulation by Protein-Protein Interaction

Abstract

Opiate drugs mediate their analgesic, euphoriant, and rewarding effects by activating opioid receptors. Pharmacological and molecular studies have demonstrated the existence of three opioid receptor subtypes, μ, δ, and κ- that couple predominantly to Gi/Go types of G proteins to regulate the activity of a diverse array of effector systems. Ample experimental evidence has demonstrated that these receptors can physically interact with a variety of accessory proteins, confirming that signal transduction of the opioid receptors is not restricted to heterotrimeric G protein activation. Such interactions can alter the effectiveness of agonist-driven cell signalling, determine the signals generated and alter the trafficking, targeting, fine tuning and cellular localization of these receptors by providing a scaffold that links the receptors to the cytoskeletal network. The current review will summarize opioid receptor interacting partners and their role as currently understood. Increasing knowledge of the mechanisms by which these interactions are regulated is expected to address problems related to phenomena such as pain perception, tolerance and dependence that occur upon chronic opiate administration and define whether disruption of such interactions may contribute to the development of novel therapeutic strategies.

RGS2 and RGS4 proteins: New modulators of the κ-opioid receptor signaling

“…all three OR subtypes (Fig. 1A) and forms helix VIII, which is proposed to 551 be the docking site of RGS4, spinophilin, periplakin, GASP and the tran-552 scription factors STAT5A/5B among others [13]. The present data indi-…”

“…κ-OR couples to PTX sensitive G proteins and has 517 the ability to interact also with various other proteins, involved in the 518 signalling, trafficking, intracellular sorting and fine tuning of this recep-519 tor [13,40]. CT and the δ-i3L indicated the ability of RGS4 to interact with μ-OR 526 and δ-OR, to modulate OR signalling [12,20].…”

Role of Phosphorylation Sites in Desensitization ofµ-Opioid Receptor

“…It could involve facilitation of recruitment of any of the many proteins that have been shown to interact directly with MOPr (Georgoussi et al, 2012).…”

“…Chu et al (2010) reported that morphine-induced, PKC-mediated desensitization is mediated partly by phosphorylation of Ga i2 subunits, which should be independent of C-terminal phosphorylation. It is possible that PKC-dependent phosphorylation of residues in the intracellular loops (Williams et al, 2013) or in other interacting proteins (Georgoussi et al, 2012) contribute to morphineinduced desensitization. Complex PKC-dependent mechanisms must contribute because calphostin C inhibited by approximately 50% in wild-type MOPr but completely abolished it in 11S/T-A.…”

Peripheral inflammatory injury alters the relative abundance of Gα subunits in the dorsal horn of the spinal cord and in the rostral ventromedial medulla of male rats

“…G protein-coupled receptors can engage multiple signaling pathways through their interactions with β-arrestins and a host of other proteins in addition to G proteins. 32–35 Moreover, different ligands acting at the same receptor can engage different subcellular signaling pathways (i.e. ligand-biased signaling).…”