Arfaxad Reyes Alcaraz
Korea University College of Medicine, South Korea
Arfaxad Reyes has his expertise in structure and stability of G-protein coupled receptors and passion for improving and creating new drug discovery platforms that greatly contribute in the development of more selective drugs with minor side effects. His studies about biased agonism in Galanin receptors help to understand the relationship between conformational structure of the receptor and its corresponding physiological effect induced by a specific ligand. Recently he and co-workers were able to develop a highly selective agonist for Galanin receptor 2 with anxiolytic effect in vivo (Arfaxad Reyes-Alcaraz et al Sci. Rep 2016) which was the base to discover how different ligand structures induce different conformations on the structure of Galanin receptors. This work greatly contribute to understand the relationship between structure and function of Galanin receptors.
Statement of the Problem: G protein coupled receptors (GPCRs) also known as seven-transmembrane receptors and are the largest family of cell-surface receptors that communicate extracellular stimuli to the cell interior (1). It is now accepted that chemically distinct ligands bind to the same GPCR and can stabilize the receptor in multiple active conformations, which results in differential activation of cell signaling pathways and, eventually, in different physiologic outcomes a phenomenon known as biased agonism (2). Biased agonism can be exploited to design drugs that selectively activate signaling pathways, leading to the desired physiologic effects while on target side effects elicited by activation of other signaling pathways via the same receptor subtype (3). Methodology & Theoretical Orientation: The aim of this study was to stablish a relationship between conformational changes in Galanin receptors and their signaling properties in living cells, for that purpose we develop a structural complementation assay based on NanoBit technology and a series of conformational fluorescein arsenical hairpin (FIASH) bioluminescence resonance energy transfer (BRET) biosensors to monitor structural changes β-arrestin 2 induced by the binding with each Galanin receptor. Findings: Here we show that Galanin receptors impose different conformational signatures in β-arrestin, moreover structurally different ligands activating the same receptor imposed different conformations in β-arrestin 2 producing biased signaling. Conclusion & Significance: Our data provide definite evidence that a receptor activated by structurally different ligands can adopt multiple active conformations. Moreover, this finding also demonstrates that functionally specific structural Galanin receptor conformations can indeed be translated to downstream effectors producing a different physiological response.