{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Corticotropin‐releasing hormone binding protein (CRHBP) is emerging as a key modulator of the corticotropin‐releasing factor (CRF) system, exerting its effects by binding CRF and related urocortin peptides with high affinity and thereby regulating the availability of free ligand that can activate CRF receptors. In the central nervous system CRHBP primarily acts as an inhibitory “buffer” that prevents excessive CRF–mediated stimulation of the hypothalamic–pituitary–adrenal (HPA) axis – for example, by attenuating CRF‐induced ACTH release from pituitary corticotropes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, in reward‐ and stress‐sensitive brain regions such as the ventral tegmental area, CRHBP is necessary for CRF’s modulation of N‐methyl‐D‐aspartate receptor synaptic transmission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic variation and epigenetic regulation of the CRHBP gene have been linked to a range of stress‐related and neuropsychiatric conditions. Several studies have reported that polymorphisms in CRHBP influence risk for depressive and suicidal behavior"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": ", as well as the effectiveness of antidepressant treatment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In parallel, alterations in CRHBP expression—due to transcriptional regulation by factors such as estrogen and inflammatory cytokines"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "or epigenetic modifications"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "—may affect arousal states and contribute to the pathogenesis of anxiety, altered electroencephalographic profiles"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", and substance use disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its central functions, CRHBP is expressed in peripheral tissues such as the placenta and cervix, where it likely plays a paracrine role in modulating CRF availability during processes like parturition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In addition, recent evidence suggests that CRHBP has roles in the modulation of pain"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "and in the regulation of stress‐induced behaviors such as binge alcohol drinking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Finally, mounting data indicate that decreased CRHBP expression—via genetic or epigenetic mechanisms—may contribute to more aggressive phenotypes in certain cancers, such as clear cell renal cell carcinoma, where down‐regulation of CRHBP is associated with diminished survival and may influence intracellular pathways controlling cell proliferation and apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight the multifaceted role of CRHBP in maintaining the balance of CRF signaling across central and peripheral systems. Its regulation appears crucial for controlling stress responses, modulating neuronal excitability and synaptic function, and influencing behavioral and physiological outcomes related to mood, addiction, pain, and even cancer progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "27"}]}, {"type": "t", "text": " Further elucidation of CRHBP’s mechanisms may offer novel therapeutic avenues for disorders associated with dysregulated stress responses.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nicole J Westphal, Audrey F Seasholtz "}, {"type": "b", "children": [{"type": "t", "text": "CRH-BP: the regulation and function of a phylogenetically conserved binding protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2741/1931"}], "href": "https://doi.org/10.2741/1931"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16368564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16368564"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mark A Ungless, Vineeta Singh, Tara L Crowder, et al. 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