GPCRs: An Emerging Link Between Cell Signaling and Therapeutic Strategies in Neurological and Metabolic Disorders

G protein-coupled receptors (GPCRs) constitute the largest and most functionally diverse family of membrane proteins, acting as master regulators of signal transduction across virtually all physiological systems. By converting extracellular stimuli into precise intracellular signaling events, GPCRs orchestrate a broad spectrum of biological processes, including neurotransmission, endocrine signaling, immune response, and metabolic homeostasis. Over recent decades, GPCRs have emerged as primary targets in drug discovery, with approximately one-third of all FDA-approved drugs modulating their activity. For instance, in neurological and metabolic disorders, aberrant GPCRs signaling has been increasingly implicated in the disease onset, progression, and therapeutic resistance. Several disorders, including Alzheimer’s, Parkinson’s, and epilepsy, as well as type 2 diabetes, obesity, and metabolic syndrome, share common signaling pathologies rooted in GPCR dysfunction. Recent breakthroughs in structural biology, ligand profiling, and computational pharmacology have informed our understanding of key aspects of GPCR conformational dynamics, biased signaling, and allosteric modulation - paving the way for more selective and efficacious therapeutic approaches. Within this receptor superfamily, orphan GPCRs - whose endogenous ligands and functions remain largely undefined - represent a frontier in receptor biology and therapeutic innovation. Despite limited characterization, emerging evidence from transgenic models, omics-based mapping, and chemical biology screens suggests these receptors may be pivotal in both central nervous system function and metabolic regulation, offering untapped therapeutic opportunities.

This Research Topic seeks to foster interdisciplinary dialogue and discovery around the roles of GPCRs in neurological and metabolic diseases. We invite contributions that bridge fundamental signaling mechanisms with translational and clinical research, encompassing both canonical and orphan GPCRs.

We welcome submissions addressing, but not limited to, the following areas:

• Mechanistic insights into GPCR signaling in neurological and metabolic pathophysiology

• High-resolution structural and dynamic analyses of GPCR-ligand interactions

• Biased signaling, functional selectivity, and allosteric modulation in drug development

• Identification and pharmacological characterization of natural and synthetic GPCR ligands

• Functional roles and therapeutic targeting of orphan GPCRs

• Advanced in vitro and in vivo models to interrogate GPCR-mediated pathways

• Clinical and translational studies targeting GPCRs in complex diseases

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: g protein-coupled receptors, GPRC, GPRCs, metabolic disorders, conformational dynamics, biased signaling, allosteric modulation, neurological disorder, Alzheimer's disease, Parkinson's disease, epilepsy, type 2 diabetes, obesity, metabolic syndrome

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.