{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Corticotropin‐releasing factor receptor type 2 (CRHR2) has emerged as a multifunctional regulator that plays context‐dependent roles in both central and peripheral systems. In the brain, activation of CRHR2 by selective urocortin peptides modulates synaptic transmission and dopaminergic activity. For example, CRHR2 signaling in the ventral tegmental area potentiates N‐methyl‐D‐aspartate receptor–mediated responses in dopamine neurons, thereby influencing reward pathways and stress‐related addictive behaviors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, CRHR2—acting together with CRHR1—regulates dopamine release in the nucleus accumbens, a mechanism that appears critical for the encoding of the emotional response to stress and may contribute to a switch from appetitive to aversive motivational states following severe stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, CRHR2 function influences sensorimotor gating, as activation enhances prepulse inhibition of the startle reflex"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and in the hippocampus, CRHR2‐mediated modulation of Mek–Erk signaling contributes to the delayed effects of stress on memory consolidation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, studies in CRHR2‐deficient mice reveal that loss of CRHR2 function is associated with enhanced anxiety‐ and depression‐like behaviors"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and altered aversive responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while chronic CRF overexpression can up‐regulate CRHR2 expression in regions such as the dorsal raphe, suggesting dynamic receptor adaptations under prolonged stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the periphery, CRHR2 is a key mediator of hormonal, cardiovascular, metabolic, angiogenic, and inflammatory processes. In pancreatic beta cells, urocortin III stimulation of CRHR2 promotes glucagon and insulin secretion via mechanisms that are blocked by CRHR2 antagonism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In skeletal muscle, urocortin 2 acting via CRHR2 appears to negatively regulate insulin‐dependent glucose uptake, thereby influencing energy balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Likewise, CRHR2‐expressing cardiomyocytes are protected against hypoxia/reoxygenation injury through activation of MAP kinase and Akt pathways, underscoring a cardioprotective role for CRHR2‐selective agonists."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In the vasculature, CRHR2 is expressed in both endothelial and smooth muscle cells, where its activation reduces vascular endothelial growth factor release and smooth muscle cell proliferation, thereby exerting a tonic inhibitory effect on angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Moreover, CRHR2 signaling in macrophages induces apoptosis via pro‐apoptotic pathways, a mechanism that may contribute to the termination of inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In the gastrointestinal tract and brain–gut axis, activation of CRHR2 inhibits gastric motor function and modulates visceral sensitivity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and within intestinal tissues, CRHR2 exerts anti‐inflammatory and anti‐angiogenic actions that contrast with the proinflammatory effects mediated by CRHR1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, the peripheral distribution of CRHR2 is further emphasized by its expression in tissues such as skin and muscle, where its selective ligand, urocortin II, is highly expressed."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Collectively, these findings highlight that CRHR2 functions as a context‐dependent modulator—facilitating stress recovery and homeostasis in the brain while concurrently orchestrating diverse endocrine, cardiovascular, metabolic, angiogenic, and anti‐inflammatory responses in peripheral tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " This array of actions positions CRHR2 as a promising target for therapeutic intervention in stress‐related disorders and metabolic diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mark A Ungless, Vineeta Singh, Tara L Crowder, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0896-6273(03)00461-6"}], "href": "https://doi.org/10.1016/s0896-6273(03"}, {"type": "t", "text": "00461-6) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12895416"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12895416"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Julia C Lemos, Matthew J Wanat, Jeffrey S Smith, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature11436"}], "href": "https://doi.org/10.1038/nature11436"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22992525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22992525"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marloes J A G Henckens, Jan M Deussing, Alon Chen "}, {"type": "b", "children": [{"type": "t", "text": "Region-specific roles of the corticotropin-releasing factor-urocortin system in stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Rev Neurosci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nrn.2016.94"}], "href": "https://doi.org/10.1038/nrn.2016.94"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27586075"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27586075"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Victoria B Risbrough, Richard L Hauger, Amanda L Roberts, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.5760-03.2004"}], "href": "https://doi.org/10.1523/JNEUROSCI.5760-03.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15269266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15269266"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Farahnaz Sananbenesi, André Fischer, Christina Schrick, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitogen-activated protein kinase signaling in the hippocampus and its modulation by corticotropin-releasing factor receptor 2: a possible link between stress and fear memory."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14673008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14673008"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tracy L Bale, Wylie W Vale "}, {"type": "b", "children": [{"type": "t", "text": "Increased depression-like behaviors in corticotropin-releasing factor receptor-2-deficient mice: sexually dichotomous responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12832554"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12832554"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Michael R Bruchas, Benjamin B Land, Julia C Lemos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0008528"}], "href": "https://doi.org/10.1371/journal.pone.0008528"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20052275"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20052275"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Aniko Korosi, Jan G Veening, Tamás Kozicz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.brainres.2005.12.034"}], "href": "https://doi.org/10.1016/j.brainres.2005.12.034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16423327"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16423327"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Chien Li, Peilin Chen, Joan Vaughan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Urocortin III is expressed in pancreatic beta-cells and stimulates insulin and glucagon secretion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2002-0087"}], "href": "https://doi.org/10.1210/en.2002-0087"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12810578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12810578"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Alon Chen, Bhawanjit Brar, Cheol Soo Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0607337103"}], "href": "https://doi.org/10.1073/pnas.0607337103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17050686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17050686"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Emmanouil Karteris, Edward W Hillhouse, Dimitris Grammatopoulos "}, {"type": "b", "children": [{"type": "t", "text": "Urocortin II is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation: potential role of the type-2 corticotropin-releasing hormone receptor in the control of myometrial contractility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2003-1210"}], "href": "https://doi.org/10.1210/en.2003-1210"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14592950"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14592950"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Tracy L Bale, Frank J Giordano, Reed P Hickey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Corticotropin-releasing factor receptor 2 is a tonic suppressor of vascularization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.102187099"}], "href": "https://doi.org/10.1073/pnas.102187099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12032352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12032352"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Christos Tsatsanis, Ariadne Androulidaki, Erini Dermitzaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Urocortin 1 and Urocortin 2 induce macrophage apoptosis via CRFR2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2005.06.057"}], "href": "https://doi.org/10.1016/j.febslet.2005.06.057"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16054139"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16054139"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yvette Tache, Muriel Larauche, Pu-Qing Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Mol Pharmacol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1874467210666170224095741"}], "href": "https://doi.org/10.2174/1874467210666170224095741"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28240194"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28240194"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Eunok Im, Sang Hoon Rhee, Yong Seek Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2010.02.055"}], "href": "https://doi.org/10.1053/j.gastro.2010.02.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20206175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20206175"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Alessandro Serra, Joy Derwenskus, Deborah L Downey, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of eye movement examination and subjective visual vertical in clinical evaluation of multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00415-003-1038-8"}], "href": "https://doi.org/10.1007/s00415-003-1038-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12736736"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12736736"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Alon Chen, Amy Blount, Joan Vaughan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Urocortin II gene is highly expressed in mouse skin and skeletal muscle tissues: localization, basal expression in corticotropin-releasing factor receptor (CRFR) 1- and CRFR2-null mice, and regulation by glucocorticoids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2003-1570"}], "href": "https://doi.org/10.1210/en.2003-1570"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14736736"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14736736"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Nina Dedic, Alon Chen, Jan M Deussing "}, {"type": "b", "children": [{"type": "t", "text": "The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Mol Pharmacol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1874467210666170302104053"}], "href": "https://doi.org/10.2174/1874467210666170302104053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28260504"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28260504"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Efi Kokkotou, Daniel Torres, Alan C Moss, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.177.5.3355"}], "href": "https://doi.org/10.4049/jimmunol.177.5.3355"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16920976"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16920976"}]}]}]}