PAC1 Receptor

The pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R) is a high-affinity, PACAP-selective G protein-coupled receptor that regulates cellular survival and homeostasis in both central and peripheral nervous systems^[1][2]. Activation of PAC1R engages multiple intracellular pathways, including adenylyl cyclase/cAMP, phospholipase C, MEK/ERK, p38 MAPK, and Akt, leading to modulation of neuronal excitability, neuroprotection, and anti-apoptotic effects^[1][3]. Compared with related VPAC1 and VPAC2 receptors, PAC1R exhibits exclusive PACAP binding, distinct intracellular signaling dynamics, and involvement in endosomal signaling microstates that influence chronic pain and stress responses^[4][5][6]. In disease models, PAC1R signaling has demonstrated neuroprotective roles in stroke, retinal injury, neurodegenerative disorders, and chronic pain, while maladaptive activation contributes to migraine, PTSD, and metabolic disorders^[1][7][8][9]. Selective agonists, such as maxadilan, enhance stem cell viability, migration, and neural differentiation by activating PAC1R-mediated Wnt/β-catenin and PKA pathways^[2]. Conversely, PAC1R antagonists and biased inhibitors targeting endosomal signaling are being explored for chronic pain, stress-related disorders, and migraine therapeutics^[9][5]. Structural and pharmacophore analyses of PAC1R facilitate the design of peptide and small-molecule modulators with isoform-selective activity, providing practical frameworks for experimental and therapeutic applications^[4][10].