P2Y₁₄ receptor in the nervous system: Pharmacology, mechanisms, and therapeutic potential

The P2Y₁₄ receptor, a nucleotide sugar-sensing G protein-coupled receptor activated primarily by UDP-glucose (UDP-G), has emerged as an important regulator of purinergic signaling in both peripheral and central tissues. Distinct from other P2Y receptors, P2Y₁₄ links extracellular metabolic cues to immune activation, chemotaxis, and inflammatory gene expression. Recent evidence demonstrates that P2Y₁₄ is widely expressed in the nervous system and contributes to neuroinflammatory responses, glial activation, and maladaptive neuronal plasticity associated with neuropathic pain and other neurological disorders. UDP-G/P2Y₁₄ signaling has been shown to promote inflammatory cascades, such as signal transducer and activator of transcription 1 (STAT1) activation. Meanwhile, pharmacological studies have identified several potent and selective P2Y₁₄ antagonists that enable precise interrogation of its pathophysiological roles. These advances highlight P2Y₁₄ as a promising therapeutic target for conditions involving neuroimmune dysregulation. This review summarizes current knowledge on P2Y₁₄ receptor structure, ligand recognition, intracellular signaling, and pharmacological development, and evaluates emerging evidence for its involvement in neuropathic pain, cerebrovascular injury, and neurodegenerative diseases. Key challenges and future directions for translating P2Y₁₄ modulation into clinical intervention are also discussed.