G-protein-coupled receptor heterodimerization modulates receptor function

Abstract

The opioid system modulates several physiological processes, including analgesia, the stress response, the immune response and neuroendocrine function. Pharmacological and molecular cloning studies have identified three opioid-receptor types, delta, kappa and mu, that mediate these diverse effects. Little is known about the ability of the receptors to interact to form new functional structures, the simplest of which would be a dimer. Structural and biochemical studies show that other G-protein-coupled receptors (GPCRs) interact to form homodimers. Moreover, two non-functional receptors heterodimerize to form a functional receptor, suggesting that dimerization is crucial for receptor function. However, heterodimerization between two fully functional receptors has not been documented. Here we provide biochemical and pharmacological evidence for the heterodimerization of two fully functional opioid receptors, kappa and delta. This results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor. Furthermore, the kappa-delta heterodimer synergistically binds highly selective agonists and potentiates signal transduction. Thus, heterodimerization of these GPCRs represents a novel mechanism that modulates their function.

Chemokines: attractive mediators of the immune response

“…GPCRs can also form heterodimers. Heterodimers of -␦-and -␦-opioid receptors exhibit not only increased sensitivity to ligand, but are also receptors with distinct functional properties [44,45]. Similar results have been reported for the somatostatin and dopamine receptors [46].…”

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

“…Since we have demonstrated that inhibition of α 2B -AR cell-surface expression is mediated through dimerization of mutant and WT receptors, it is possible that the inhibitory effect of α 2B -ARm on the transport of α 2A -AR and α 2C -AR is also due to heterodimerization of α 2B -ARm with α 2A -AR or α 2C -AR. This possibility is supported by a number of observations demonstrating that closely related members of G protein-coupled receptors may heterodimerize [11,14,[37][38][39]. Furthermore, α 2A -AR and α 2C -AR indeed form heterodimers with β 1 -AR and M 3 -muscarinc receptor, respectively [40,41].…”

“…Therefore, dimers are unable to export from the ER. Dimerization has been well described for a variety of G protein-coupled receptors [9][10][11][12][13][14][15][34][35][36][37][38][39][40][41]. However, whether α 2B -AR is capable of forming homodimers has not been reported.…”

In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties

“…Studies have demonstrated that opioid receptor dimerization alters signaling (5)(6)(7)(8), trafficking (5,9), and internalization (10). It also has been suggested that opioid receptor heterodimers could explain pharmacological subtypes (3), such as δ 1 (Deltorphin II) respectively, yet, these same subtypes have not been found utilizing cloning methods.…”