CRFR1

CRFR1 (corticotropin-releasing factor receptor 1, CRHR1) is a class B G protein-coupled receptor that binds corticotropin-releasing hormone (CRH) and urocortin, serving as a central regulator of endocrine, autonomic, behavioral, and immune responses to stress^[1][2]. Mechanistically, CRFR1 predominantly couples to G_s proteins, activates adenylyl cyclase, increases cAMP production, and engages downstream PKA, PKC, and MAPK signaling pathways that shape tissue-specific stress responses^[1][3]. Within the hypothalamic-pituitary-adrenal (HPA) axis, CRFR1 signaling in pituitary corticotrophs promotes ACTH release and coordinates neuroendocrine adaptation to stress exposure^[1][4]. In disease-relevant models, genetic deletion or pharmacological inhibition of CRFR1 reduces anxiety-like behavior and blunts stress reactivity, supporting its role in stress-related neuropsychiatric disorders^[1][4][5]. CRFR1 also regulates neuronal excitability, fear learning, memory-related processes, and GABAergic transmission in limbic circuits that are frequently disrupted during chronic stress and alcohol dependence^[1][5][6]. Compared with the related isoform CRFR2, CRFR1 displays broader forebrain and pituitary expression, higher functional involvement in stress initiation, and distinct ligand selectivity, whereas CRFR2 is more closely associated with stress recovery and peripheral regulation^[1][7]. For experimental applications, selective CRFR1 antagonists, including antalarmin, CP-154,526, and DMP-696, are widely used to investigate stress signaling, anxiety phenotypes, and HPA-axis dysregulation in preclinical models^[5][8].