The Old and New Visions of Biased Agonism Through the Prism of Adenosine Receptor Signaling and Receptor/Receptor and Receptor/Protein Interactions

Abstract

Biased signaling is a concept that has arisen in the G protein-coupled receptor (GCPR) research field, and holds promise for the development of new drug development strategies. It consists of different signaling outputs depending on the agonist’s chemical structure. Here we review the most accepted mechanisms for explaining biased agonism, namely the induced fit hypothesis and the key/lock hypothesis, but we also consider how bias can be produced by a given agonist. In fact, different signaling outputs may originate at a given receptor when activated by, for instance, the endogenous agonist. We take advantage of results obtained with adenosine receptors to explain how such mechanism of functional selectivity depends on the context, being receptor-receptor interactions (heteromerization) one of the most relevant and most studied mechanisms for mammalian homeostasis. Considering all the possible mechanisms underlying functional selectivity is essential to optimize the selection of biased agonists in the design of drugs targeting GPCRs.

Expression of the Adenosine A2A-A3 Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APPSw,Ind Alzheimer’s Disease Model

“…Functional selectivity in the form of biased agonism or else is dependent on the context of GPCR, especially if the receptor is part of a heteromer. Our results confirm that signaling via A 2A R or A 3 R varies depending on the context, that is, on the structure of the heteromer and/or allosteric interactions with G and scaffold proteins [ 86 , 87 ]. Otherwise, it would be difficult to interpret why the signal is more robust in resting than in activated microglia although the expression of the heteromer is similar.…”

Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties

“…In fact, obesity is not only considered an epidemic (see literature 66 for recent review), but it also shares characteristics of drug addiction. Furthermore, the possibility of biased signaling 67–70 combined with targeting dopamine and ghrelin receptor‐containing functional units opens up new avenues for the treatment of addiction and/or eating disorders.…”

Adenosine A2A Receptors as Biomarkers of Brain Diseases

“…This is certainly an area of research that might open new avenues to design neuroprotective strategies linked to A 2A R. The association of A 2A R up-regulation with brain diseases offers another promising opportunity to develop informative biomarkers of the susceptibility and/or evolution of different brain diseases once PET ligands are optimized to detect extrastriatal A 2A R. In fact, A 2A R throughout the brain are most abundant in the striatum (reviewed in Svenningsson et al, 1999) and the available PET ligands have been optimized to detect striatal A 2A R (e.g., Mishina et al, 2011;Ishibashi et al, 2018); however, this population of A 2A R has a different pharmacology (Orrú et al, 2011;Cunha, 2016), a different adaptive profile (Cunha et al, 1995) and a different role in most brain conditions (Shen et al, 2008(Shen et al, , 2013Yu et al, 2008;Wei et al, 2014). Thus, it is likely that the currently available PET ligands might not be useful to assess modifications of extra-striatal A 2A R. New cortical A 2A Rdirected PET ligands need to be designed based on the particular properties and interacting partners of cortical A 2A R (reviewed in Franco et al, 2020) to allow an in vivo detection of A 2A R upsurge as potential general biomarkers of brain dysfunction (Sun et al, 2020).…”