Rising Star: G Protein-coupled Receptors (GPCRs) in Microenvironment Pharmacology and Sensory Perception Pharmacology

Professor Jinpeng Sun has long been dedicated to pharmacological research on G protein-coupled receptors (GPCRs), achieving systematic advances in areas such as ligand-receptor recognition, drug target validation, and membrane receptor-based drug development. In 2007, he earned his Ph.D. in Molecular Pharmacology from the Albert Einstein College of Medicine, after which he conducted postdoctoral research in the laboratory of Nobel Laureate Professor Robert J. Lefkowitz at Duke University, a pioneering figure in GPCR biology. In 2011, Professor Sun established his independent research group in China, where he has since pursued in-depth investigations into GPCR pharmacology. To address key bottlenecks in GPCR drug discovery, such as the unclear pathophysiological hubs of complex diseases and the difficulty in designing selective drugs, Professor Sun's team proposed that the dynamic and multiple interactions among ligands, receptors, and intracellular (membrane) effectors are important players in microenvironment establishment and adjustment that drive or modulate disease progresses. Based on this conceptual framework, they developed a suite of innovative methodologies, including endogenous ligand capture technology, highly sensitive multipathway GPCR activity profiling systems, and microscale force activation platforms. Using these tools, the team successfully identified membrane receptors for several critical hormones and metabolites, such as glucocorticoids, androgens, progesterone, and ceramides, resolving several long-standing questions in pharmacology. They were the first to discover the GPCR responsible for the sense of balance and elucidated the molecular mechanisms through which GPCRs sense mechanical force, odors, pruritic stimuli, and acidic or alkaline environments, substantially expanding the known functional scope of GPCR biology. Furthermore, by integrating chemical biology with signaling assays, Professor Sun's group introduced theoretical models such as the "flute model" of functional coding of GPCR phosphorylation and "proline regions docking and sorting" for GPCR biased signaling. Exploiting AI-guided ligand design, Sun's group developed over 20 selective lead compounds targeting the GPCRs involved in psychiatric, metabolic, cardiovascular, and aging-related disorders. Several candidates have completed preliminary pharmacokinetic and toxicity studies, demonstrating strong translational potential. This article systematically summarizes the key scientific contributions from Professor Sun Jinpeng's laboratory over the past decade, highlighting their impact on receptor-ligand paring, signaling mechanism elucidation, tool development, and rational drug design, and discusses their implications for the future of precision medicine.