GPCR signaling from a primary cilium perspective

G protein-coupled receptors (GPCRs) are best known for initiating signaling at the plasma membrane, yet a substantial and functionally distinct subset of these receptors localizes to the primary cilium, a highly specialized cell-surface organelle. Over the past decade, the primary cilium has emerged as a privileged signaling compartment that concentrates GPCRs, signaling effectors, and second messengers within a physically constrained and biochemically unique environment. In this review, we synthesize current knowledge of GPCR signaling from a primary cilium perspective, with emphasis on receptor repertoire, trafficking mechanisms, and compartment-specific signal transduction. We discuss how ciliary entry and exit are regulated by dedicated transport systems, how canonical GPCR signaling components-G proteins, GPCR kinases, β-arrestins, regulators of G protein signaling, and A-kinase anchoring proteins-are organized within cilia, and how the ciliary geometry, membrane composition, voltage, pH, and cytoskeletal architecture shape signaling outcomes. We further highlight how cilia support autonomous and highly sensitive microdomains of cAMP and calcium (Ca²⁺) signaling, enabling integration and hierarchical control of multiple GPCR inputs. Finally, we examine the physiological consequences of ciliary GPCR signaling in neural, renal, adipose, and pancreatic and developmental tissues, where defects in ciliary signaling contribute to metabolic disease, impaired morphogenesis, and tissue homeostasis, and ciliopathies-a range of human disorders arising from primary cilium dysfunction. Together, these studies establish the primary cilium as a dynamic and modular GPCR signaling hub and underscore the importance of subcellular localization in determining receptor function and signaling specificity. SIGNIFICANCE STATEMENT: Beyond their traditional role at the plasma membrane, many GPCRs signal from primary cilia, specialized cellular compartments that create unique signaling environments. This review synthesizes advances in ciliary GPCR trafficking, organization, and signal transduction, showing how subcellular localization determines receptor function and how disrupted ciliary signaling contributes to human diseases, including ciliopathies, metabolic disorders, and developmental defects.