GPCR Receptor Complexes: Emerging Therapeutic Paradigms in Neuropsychiatry

G protein-coupled receptors (GPCRs) represent the largest pharmacologically exploited receptor superfamily in the human genome, accounting for the targets of approximately 35% of all approved drugs. In neuropsychiatry, GPCRs have long underpinned therapeutic strategies across a broad disease spectrum, from dopamine and serotonin receptor-based antipsychotics and antidepressants to opioid receptor-targeting therapies for addiction and pain. Despite this legacy, the conventional “one drug, one receptor” model has shown fundamental limitations: incomplete efficacy, dose-limiting side effects, high inter-individual variability, and persistent treatment resistance continue to burden clinical neuropsychiatric practice.Evidence from structural biology, biophysical imaging, and molecular pharmacology has established that GPCRs do not operate as isolated monomeric units. Instead, they form dynamic receptor complexes, including homodimers, heteromers, and higher-order oligomeric assemblies, with distinct conformational states, signaling signatures, trafficking behaviors, and pharmacological profiles that diverge substantially from those of their individual components. Critically, GPCR heteromers have been detected in vivo in brain regions of direct relevance to neuropsychiatric disease, including the striatum, prefrontal cortex, hippocampus, and limbic system. Beyond canonical class GPCRs, non-classical entities such as the sigma-1 receptor further expand this heteromeric landscape, engaging both GPCR and ion-channel partners to modulate neuropsychiatric circuits.This Research Topic aims to consolidate and advance this rapidly evolving field by integrating perspectives from molecular neuropharmacology, structural neuroscience, systems biology, and translational psychiatry. By moving beyond the monomeric receptor paradigm, this collection will provide a timely and comprehensive resource for researchers and clinicians working at the frontier of neuropsychiatric drug discovery.This Research Topic invites contributions across the following key themes:- Neuropharmacology of GPCR Heteromers across Brain Circuits and Receptor Systems How specific receptor complexes, including dopamine, serotonin, adenosine, opioid, cannabinoid, and glutamate receptor heteromers, as well as complexes involving non-canonical GPCRs such as the sigma-1 receptor shape signaling in brain regions relevant to neuropsychiatric disease, and how their pharmacological properties diverge from those of individual receptor components.- Signaling Pharmacology and Drug Mechanisms at GPCR ComplexesHow heterodimerization drives biased agonism, G protein selectivity shifts, and β-arrestin recruitment in neurons; and how the mechanisms of classical and emerging neuropsychiatric drugs (antipsychotics, antidepressants, opioids, and allosteric modulators) can be reinterpreted through the lens of receptor complex pharmacology.-Novel Therapeutic Strategies Targeting GPCR Complexes The design and validation of bivalent ligands, bitopic compounds, peptide disruptors, and nanobodies capable of selectively engaging heteromeric interfaces, with particular emphasis on improving CNS selectivity, reducing side effects, and overcoming treatment resistance.- Receptor Complex Dysregulation in Neuropsychiatric and Neurodegenerative Disease How altered GPCR complex expression, stoichiometry, and function contribute to the pathophysiology of schizophrenia, major depressive disorder, addiction, Parkinson’s disease, and Alzheimer’s disease, drawing on both post-mortem human brain data and preclinical disease models.- Methodological Advances and Translational Perspectives Cutting-edge tools for detecting and characterizing receptor complexes in brain tissue (including PLA, BRET/FRET, cryo-EM, and iPSC-derived neuronal models) alongside translational efforts to bring GPCR complex-targeting strategies from bench to clinical application. Topic editors: Jing-Ya Wang, Agnieszka Zagórska, Yunfeng Li Source: https://www.frontiersin.org/research-topics/83737/gpcr-receptor-complexes-emerging-therapeutic-paradigms-in-neuropsychiatry