No abstract

Neuroprotective M2‐skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein‐coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A2A (A2AR) and cannabinoid CB2 (CB2R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB2R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A2AR antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A2A‐CB2 receptor heteromer (A2A‐CB2Het). Particularly relevant is the upregulation of A2A‐CB2Het expression in samples from the APPSw,Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A2A receptors results in increased CB2R‐mediated signaling. This heteromer‐specific feature suggests that A2AR antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.

Functional selectivity is a property of G-protein-coupled receptors (GPCRs) by which activation by different agonists leads to different signal transduction mechanisms. This phenomenon is also known as biased agonism and has attracted the interest of drug discovery programs in both academy and industry. This relatively recent concept has raised concerns as to the validity and real translational value of the results showing bias; firstly biased agonism may vary significantly depending on the cell type and the experimental constraints, secondly the conformational landscape that leads to biased agonism has not been defined. Remarkably, GPCRs may lead to differential signaling even when a single agonist is used. Here we present a concept that constitutes a biochemical property of GPCRs that may be underscored just using one agonist, preferably the endogenous agonist. “Biased receptor functionality” is proposed to describe this effect with examples based on receptor heteromerization and alternative splicing. Examples of regulation of final agonist-induced outputs based on interaction with β-arrestins or calcium sensors are also provided. Each of the functional GPCR units (which are finite in number) has a specific conformation. Binding of agonist to a specific conformation, i.e. GPCR activation, is sensitive to the kinetics of the agonist-receptor interactions. All these players are involved in the contrasting outputs obtained when different agonists are assayed.