The antioxidant resveratrol acts as a non-selective adenosine receptor agonist.

Resveratrol (RSV) is a natural polyphenolic antioxidant with a proven protective role in several human diseases involving oxidative stress, although the molecular mechanism underlying this effect remains unclear. The present work tried to elucidate the molecular mechanism of RSV's role on signal transduction modulation. Our biochemical analysis, including radioligand binding, real time PCR, western blotting and adenylyl cyclase activity, and computational studies provide insights into the RSV binding pathway, kinetics and the most favored binding pose involving adenosine receptors, mainly A2A subtype. In this study, we show that RSV target adenosine receptors (AdoRs), affecting gene expression, receptor levels, and the downstream adenylyl cyclase (AC)/PKA pathway. Our data demonstrate that RSV activates AdoRs. Moreover, RSV activate A2A receptors by directly binding to the classical orthosteric binding site. Intriguingly, RSV-induced receptor activation can stimulate or inhibit AC activity depending on concentration and exposure time. Such subtle and multifaceted regulation of the AdoRs/AC/PKA pathway might contribute to the protective role of RSV. Our findings suggest that RSV molecular action is mediated, at least in part, by activation of adenosine receptors and create the opportunity to interrogate the therapeutic use of RSV in pathological conditions involving AdoRs, such as Alzheimer.

Molecular modeling and simulation of membrane lipid-mediated effects on GPCRs.

Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding of the modulation of GPCR by membrane lipids is not available. However, specific receptor-lipid interactions as well as unspecific effects mediated by the bulk properties of the membrane (thickness, curvature, etc.) have been proposed to be key regulators of GPCR modulation. In this review, we examine computational efforts made towards modeling and simulation of (i) the complex behavior of membrane lipids, (ii) membrane lipid-GPCR interactions as well as membrane lipid-mediated effects on GPCRs and (iii) GPCR oligomerization in a native-like membrane environment. We propose that, from the perspective of computational modeling, all three of these components need to be addressed in order to achieve a deeper understanding of GPCR functioning. Presently, we are able to simulate numerous lipid properties applying advanced computational techniques, although some barriers, such as the time-length of these simulations, need to be overcome. Implementing three-dimensional structures of GPCRs in such validated membrane systems can give novel insights in membrane-dependent receptor modulation and formation of higher order receptor complexes. Finally, more realistic GPCR-membrane models would provide a very useful tool in studying receptor behavior and its modulation by small drug-like ligands, a relevant issue for drug discovery.

Crosstalk within GPCR heteromers in schizophrenia and Parkinson's disease: physical or just functional?

Crosstalk between G protein-coupled receptors (GPCRs) is one of the key mechanisms used by the cell for integrating multiple signaling pathways. Functional crosstalk at the level of signaling pathways was initially thought to regulate receptor function. Importantly, the existence of GPCR heteromers demonstrates that direct physical interactions between GPCRs could also be behind the crosstalk phenomenon. Neurological disorders such as Parkinson's disease (PD) and schizophrenia have been linked to a dysfunctional communication between certain GPCRs. In this review, we discuss functional and physical crosstalk of the main GPCR families involved in the aforementioned disorders. In addition, we analyze the available structural information on physical crosstalk and highlight some strategies in drug discovery based on these crosstalk mechanisms.