Revolution in GPCR signalling: opioid receptor heteromers as novel therapeutic targets: IUPHAR Review 10

Abstract

GPCRs can interact with each other to form homomers or heteromers. Homomers involve interactions with the same receptor type while heteromers involve interactions between two different GPCRs. These receptor–receptor interactions modulate not only the binding but also the signalling and trafficking properties of individual receptors. Opioid receptor heteromerization has been extensively investigated with the objective of identifying novel therapeutic targets that are as potent as morphine but without the side effects associated with chronic morphine use. In this context, studies have described heteromerization between the different types of opioid receptors and between opioid receptors and a wide range of GPCRs including adrenoceptors, cannabinoid, 5‐HT, metabotropic glutamate and sensory neuron‐specific receptors. Recent advances in the field involving the generation of heteromer‐specific reagents (antibodies or ligands) or of membrane‐permeable peptides that disrupt the heteromer interaction are helping to elucidate the physiological role of opioid receptor heteromers and the contribution of the partner receptor to the side effects associated with opioid use. For example, studies using membrane‐permeable peptides targeting the heteromer interface have implicated μ and δ receptor heteromers in the development of tolerance to morphine, and heteromers of μ and gastrin‐releasing peptide receptors in morphine‐induced itch. In addition, a number of ligands that selectively target opioid receptor heteromers exhibit potent antinociception with a decrease in the side effects commonly associated with morphine use. In this review, we summarize the latest findings regarding the biological and functional characteristics of opioid receptor heteromers both in vitro and in vivo.

Selective and Wash‐Resistant Fluorescent Dihydrocodeinone Derivatives Allow Single‐Molecule Imaging of μ‐Opioid Receptor Dimerization

“…Interestingly, in the above studies μ‐ORs were found to crystallize as dimers . Largely based on previous experiments applying resonance energy transfer methods, these findings support the hypothesis that μ‐ORs might form homodimers . However, the nanoscale organization and dynamics of μ‐ORs on the surface of living cells remain largely unknown, mostly due to technical limitations of conventional methods.…”

Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

“…46,83 Further, the impact of a 5-HT 2A R:5-HT 2C R protein complex on neuronal firing is not known and it is wholly possible that the biochemical, signaling, and pharmacological properties of the protein complex diverge from that of the single receptor, although this is a controversial and active research topic. 84–87 Thus, while future research is required to tease apart the relative role of these two GPCRs within the same neurons versus interacting neurons in the mPFC, altered firing of GABA neurons which colocalize the 5-HT 2A R and 5-HT 2C R may dysregulate pyramidal outflow to drive motor impulsivity. The fact that systemic administration of 5-HT 2A R and the 5-HT 2C R ligands oppositionally control motor impulsivity 9,11–20,22–26 (and other behaviors) 88 adds further impetus to disentangling the mechanisms through which these receptors control neuronal output to mediate behaviors that contribute to chronic health disorders ( e.g ., drug addiction, attention deficit disorder, autism, and obesity/binge eating disorder).…”

Molecular Pharmacology ofδ-Opioid Receptors

“…The concept has now extended to rhodopsin-like class A GPCRs. As extensively reviewed recently, receptor heterooligomers are independent entities with distinct properties and regulation (Fujita et al, 2014(Fujita et al, , 2015Gomes et al, 2016).…”