G protein-coupled receptor heteromers are key players in substance use disorder

Abstract

G protein-coupled receptors (GPCR) represent the largest family of membrane proteins in the human genome. Physical association between two different GPCRs is linked to functional interactions which generates a novel entity, called heteromer, with specific ligand binding and signaling properties. Heteromerization is increasingly recognized to take place in the mesocorticolimbic pathway and to contribute to various aspects related to substance use disorder. This review focuses on heteromers identified in brain areas relevant to drug addiction. We report changes at the molecular and cellular levels that establish specific functional impact and highlight behavioral outcome in preclinical models. Finally, we briefly discuss selective targeting of native heteromers as an innovative therapeutic option.

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

“…For instance, these genetically modified animals are, by themselves, not sufficient to determine whether the constitutive activity of GPCRs, their oligomerization, or their coupling through G protein and/or βarrestins mediates alcohol actions. Combining complex pharmacological, biophysical tools together with knockout and conditional mutant mice [7,22,24,25] could help to cast light on the molecular mechanisms underlying GPCR signaling in alcohol-related behaviors. As mentioned above, the powerful potential of such combined strategies was recently illustrated by Godlewski et al [23] reporting a functional crosstalk between the endocannabinoid and the ghrelin systems to promote alcohol intake through activation of the gastric vagalbrain axis.…”

“…Oligomerization may change the ligand binding and signaling properties of the GPCRs and thus can result in unique functional entities [5,6]. Interestingly, GPCR heterodimers have been described in different structures of the rodent brain and are believed to contribute to several features of substance use disorder [7].…”

The Balance of MU-Opioid, Dopamine D2 and Adenosine A2A Heteroreceptor Complexes in the Ventral Striatal-Pallidal GABA Antireward Neurons May Have a Significant Role in Morphine and Cocaine Use Disorders

“…Therefore, the inhibitory signaling of the D2R can even become increased helping to maintain a certain degree of increase in the GABA antireward neurons. It is not clear to which degree the DOR protomer operating via Gi/o can take over inhibitory function of the MOR protomer upon treatment with naloxone (Stockton and Devi, 2012;Derouiche and Massotte, 2019).…”

“…Thus, there should be a balance between these two types of D2R heteroreceptor complexes in the antireward neurons. In addition, they can also contain MOR-δ opioid receptor (DOR) heteroreceptor complexes which have been observed in rodents and are important targets for morphine [see e.g., (Gomes et al, 2000;Gupta et al, 2010;Borroto-Escuela et al, 2013c;Kabli et al, 2014;Erbs et al, 2016;Derouiche and Massotte, 2019)] (Figure 1). There should also exist a balance between these two types of MOR complexes present in the antireward neurons.…”

Comparison of Various Selection Strategies Used for Isolation of Human Monoclonal scFv Antibody Specific to GPCRs Heteromers

“…Such strategy allows to obtain a tissue-specific acting, since the interaction between receptors engaged in the complex formation can only take place when the receptors are simultaneously expressed on the same cell. Recent data indicate the existence of clinically relevant GPCRs heteromers, important in the treatment of, among others, pain, asthma or Parkinson's disease [3][4][5][6][7].…”