Molecular and Structural Determinants of Endogenous Peptide-GPCR Signaling

Endogenous peptides are fundamental mediators of endocrine and neuroendocrine communication, coordinating hormone action, secretion, and cellular responses across a broad range of physiological systems. Many of these effects are mediated through G protein-coupled receptors (GPCRs), which translate peptide binding into highly specific intracellular signaling programs. As a result, peptide-responsive GPCRs occupy a central position in endocrine biology, linking ligand structure to receptor activation, signaling selectivity, and functional output.In recent years, major advances in structural biology, molecular pharmacology, and quantitative signaling have reshaped our understanding of how endogenous peptides engage GPCRs. High-resolution studies have revealed new details of peptide-receptor recognition, conformational transitions associated with receptor activation, and the structural basis of pathway-selective signaling. At the same time, growing evidence indicates that endogenous peptides can drive distinct signaling, trafficking, and regulatory responses depending on ligand sequence, receptor context, subcellular localization, and cellular state.Despite this progress, important questions remain unresolved. The molecular determinants of peptide binding and receptor activation, the mechanisms underlying signaling specificity and biased agonism, and the contribution of receptor trafficking and spatiotemporal signaling to endocrine function are still incompletely understood. In addition, pathological alterations affecting peptide ligands, GPCR structure, or downstream signaling components may profoundly reshape endocrine signaling networks, yet these mechanisms remain insufficiently characterized.A deeper understanding of endogenous peptide signaling through GPCRs will be essential to define the molecular basis of endocrine regulation and disease, and to support the development of more selective pharmacological strategies. This Research Topic aims to bring together cutting-edge research that advances the mechanistic, structural, and translational understanding of endogenous peptide-GPCR systems, from ligand recognition and receptor activation to intracellular signaling dynamics and therapeutic targeting.To gather further insights into this rapidly evolving field, we welcome original research, review, and perspective articles addressing, but not limited to, the following themes:• Molecular mechanisms of endogenous peptide binding, GPCR activation, and signal transduction• Structural analysis of peptide-GPCR complexes and conformational determinants of receptor function• Allosteric regulation, biased agonism, and mechanisms of signaling specificity• Quantitative aspects of receptor activation, signaling kinetics, and computational modeling• Receptor trafficking, endocytosis, exocytosis, and compartmentalized signaling• Links between peptide-GPCR signaling and hormone secretion or endocrine cell function• Structural and functional consequences of pathological alterations in peptide ligands, receptors, and downstream signaling proteins• Translational and pharmacological approaches informed by mechanistic and structural discoveriesProf. Juan J. Perez is the owner of a small participation in Allinky Biopharma. Prof. Alejandra Tomas Catala has received research grant funding from Eli Lilly and Sun Pharmaceuticals. Topic editors: Juan Jesus Perez, Xavier Iturrioz, Alejandra Tomas Catala Source: https://www.frontiersin.org/research-topics/81214/molecular-and-structural-determinants-of-endogenous-peptide-gpcr-signaling