{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADCYAP1R1 encodes the pituitary adenylate cyclase‐activating polypeptide type I receptor (PAC1R), a multifunctional class B G protein–coupled receptor that mediates a broad range of PACAP effects in both the central nervous system and peripheral tissues. A series of studies have demonstrated that PAC1R is essential for regulating stress responses, fear processing, and neuroendocrine adaptation—with common genetic variants (e.g., rs2267735) showing sex‐specific associations with posttraumatic stress disorder that are thought to be driven by estrogen‐dependent transcriptional mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": " Structural and biochemical analyses have elucidated the molecular interactions between PACAP and the extracellular domain of PAC1R, revealing how hormone binding initiates intracellular signaling pathways—including activation of adenylyl cyclase, phospholipase C, and the ERK cascade."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": " In addition, PAC1R signaling contributes to neural stem cell proliferation, synaptic plasticity, and memory formation, and it plays a neuroprotective role in models of ischemia, spinal cord injury, and pulmonary hypertension."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": " Epigenetic modifications of ADCYAP1R1, as well as genetic variation, have been linked not only to neuropsychiatric conditions but also to respiratory and metabolic dysregulation such as asthma and childhood obesity"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": ", while additional work has implicated ADCYAP1R1 variation in susceptibility to cluster headache."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Collectively, these findings underscore the pivotal role of ADCYAP1R1/PAC1R in orchestrating stress, inflammatory, and neuroprotective signaling—with important implications for treating neuropsychiatric, cardiovascular, and metabolic disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kerry J Ressler, Kristina B Mercer, Bekh Bradley, et al. 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