Disease-Specific Heteromerization of G-Protein-Coupled Receptors That Target Drugs of Abuse

Abstract

Drugs of abuse such as morphine or marijuana exert their effects through the activation of G-protein-coupled receptors (GPCRs), the opioid and cannabinoid receptors, respectively. Moreover, interactions between either of these receptors have been shown to be involved in the rewarding effects of drugs of abuse. Recent advances in the field, using a variety of approaches, have demonstrated that many GPCRs, including opioid, cannabinoid, and dopamine receptors, can form associations between different receptor subtypes or with other GPCRs to form heteromeric complexes. The formation of these complexes, in turn, leads to the modulation of the properties of individual protomers. The development of tools that can selectively disrupt GPCR heteromers as well as monoclonal antibodies that can selectively block signaling by specific heteromer pairs has indicated that heteromers involving opioid, cannabinoid, or dopamine receptors may play a role in various disease states. In this review, we describe evidence for opioid, cannabinoid, and dopamine receptor heteromerization and the potential role of GPCR heteromers in pathophysiological conditions.

G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives

“…In this regard, the receptor heteromer would be disease specific Gomes et al, 2013a). The dopamine D 1 -D 3 receptor heteromer seems to be involved in the very common and troublesome secondary effect of L-dopa treatment in Parkinson's disease, L-dopa-induced dyskinesia (reviewed in Ferré et al, 2010).…”

“…These are all properties that are now eagerly pursued in possibly new marketable compounds. Very few studies have addressed the search for receptor-heteromer selective compounds, which is quite surprising given the continuous discovery of functionally significant receptor heteromers (for recent review, see Gomes et al, 2013a). Compounds or reagents (monovalent antibodies or membrane permeant peptides) specifically targeting the heteromer interface are likely not only to serve as much needed tools to explore the physiologic significance of GPCR heteromers, but also serve as "leads" for development of highly selective drugs for the treatment of a variety of disorders.…”

Oligomerization of GPCRs involved in endocrine regulation

“…Moreover, bivalent ligands (illustrated in cell type 2) combine particular ligands for the respective protomers, which may ultimately lead to alterations in the signaling properties of the complex (response G). , Rashid et al 2007, Gomes et al 2013); (iv) bind ligand(s) that differ (e.g. also at allosteric binding sites) (Durroux 2005); (v) bind artificial ligands that modify signaling pathways such as bivalent ligands (Shonberg et al 2011, Mohr et al 2013, Yuan et al 2013.…”

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…This finding led to the suggestion (Fuxe et al, , 2014aGomes et al, 2013) that RRI could open new targets for drug development and allow new strategies of treatment. This aspect is presently the subject of intense research (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for recent reviews).…”

“…This aspect is presently the subject of intense research (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for recent reviews). In recent years, such an effort allowed the characterization of a panel of receptor complexes representing possible targets for the treatment of pathologic conditions, such as Parkinson's disease , schizophrenia and depression Sahlholm et al, 2017), neuropathic pain , addiction (Gomes et al, 2013), and food intake disorders (Kern et al, 2012). On this basis, novel strategies for drug treatment have also been proposed.…”