GPR149 (G protein-coupled receptor 149): Structure, signaling, and emerging roles in reproduction, metabolism, and...

G protein-coupled receptors (GPCRs) constitute one of the largest and most versatile families of membrane proteins, mediating a wide range of physiological functions through intracellular signaling pathways. Among them, G protein-coupled receptor 149 (GPR149) is an orphan receptor that has recently attracted increasing attention due to its distinctive structure and emerging biological roles. Although initially identified as an "antifertility" gene with high ovarian expression, accumulating evidence suggests a broader physiological relevance, including roles in metabolic and neurological regulation. This narrative review summarizes and integrates current evidence on the structure, expression patterns, and functional roles of GPR149 across multiple biological systems, including reproduction, metabolism, and the central nervous system (CNS), while highlighting existing knowledge gaps and future research directions. GPR149 appears to act as a negative regulator of fertility and ovulation, influencing oocyte maturation and granulosa cell signaling. In metabolic regulation, GPR149 deficiency is associated with resistance to diet-induced obesity and improved insulin sensitivity. In the nervous system, GPR149 expression in glial and neuronal populations has been linked to myelination and neuroendocrine signaling, primarily through modulation of the MAPK/ERK pathway. Altered expression of GPR149 under diabetic and neurological conditions further supports its multifunctional role. Collectively, current evidence positions GPR149 as a multifunctional orphan GPCR involved in the regulation of reproductive, metabolic, and neural processes. Elucidating its ligand interactions and signaling mechanisms may open new therapeutic avenues for reproductive disorders, metabolic syndromes, and neurodegenerative diseases.