Functional Autoantibodies Against G-Protein-Coupled Receptors: Insights into Molecular Mechanisms, Clinical Relevance and Therapeutic Perspectives

G-protein-coupled receptors (GPCRs) represent the largest superfamily of membrane-bound receptors in the human organism and are involved in the regulation of numerous physiological processes in almost all organ systems. Characterized by seven transmembrane domains and coupling to heterotrimeric G-proteins, they mediate signal transduction between extracellular stimuli and intracellular responses. Through these mechanisms they regulate critical processes such as cardiovascular function, neurotransmission, immune function, endocrine secretion, and metabolic homeostasis. Growing evidence suggests that functional autoantibodies directed against GPCRs (GPCR-fAAbs) may contribute to the pathophysiology of various diseases. By binding to extracellularly accessible regions of their target receptors, these antibodies can directly modulate receptor function and intracellular signaling. Depending on the receptor, epitope, and functional properties of the autoantibody, GPCR-fAAbs can act as agonists and activate receptor function or as antagonists and inhibit receptor function or alter the receptor signaling. Importantly, the presence of GPCR-directed autoantibodies does not necessarily indicate functional activity or pathogenicity, and their biological effects may depend on both autoantibody-specific and cellular factors. The potential role of GPCR-fAAbs has been described in a growing number of autoimmune and non-autoimmune diseases affecting various organ systems. This review article aims to provide a comprehensive overview of the current knowledge on GPCRs and GPCR-fAAbs focusing on their molecular mechanisms, functional characteristics, and potential pathophysiological roles in various diseases. Furthermore, current detection methods, clinical findings and established and emerging therapeutic strategies, including immunoadsorption (IA), aptamer-based neutralization, receptor blocking, and targeted B cell modulation, are critically discussed. Although all these approaches present certain challenges in their application, specific prospects for clinical implementation can be highlighted. Overall, GPCR-fAAbs represent an increasingly recognized pathophysiological factor with potential clinical implications, while their targeted therapeutic modulation remains an evolving area of translational research.