A superconserved orphan GPCR in brain function and disease: insights into GPR85

G protein‑coupled receptor 85 (GPR85), also known as superconserved receptor expressed in brain 2 (SREB2), is a highly conserved orphan class A G protein-coupled receptors (GPCR) with preferential expression in the central nervous system (CNS). Since its identification, GPR85 has emerged as a critical regulator of neuronal development, synaptic function, and circuit excitability, with accumulating evidence implicating its involvement in cognitive and behavioral processes. Moreover, further studies have linked dysregulation of GPR85 to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD), highlighting its potential relevance to human brain disease. In this review, we summarize current knowledge of GPR85 biology by integrating findings from animal models with emerging evidence from human studies as well as our analyses of publicly available human single-nucleus and spatial transcriptomic datasets to refine current understanding of GPR85 organization in the human brain. Together, these perspectives support a revised view of GPR85 as a context-dependent modulator of brain function operating across multiple cellular systems, highlighting the need to determine its roles in brain physiology, pathology, and therapeutic targeting.