Disease relevance of Crhr1

• Body weight reduction during Ucn infusion paralleled food intake in wild-type mice, but persisted throughout the infusion in CRFR1-/- mice [1].
• Reduced cerebral injury in CRH-R1 deficient mice after focal ischemia: a potential link to microglia and atrocytes that express CRH-R1 [2].
• Use of the G(i) and G(o) protein inhibitor pertussis toxin showed that ERK1/2-p42, 44 activation by Ucn-I via CRFR1 and CRFR2beta are both G(i) and/or G(o) protein dependent [3].
• We investigated the CRF receptor subtypes involved in gastric postoperative ileus [4].
• It is suggested that phospholipid methylation may be a CRF receptor-mediated event associated with ACTH release in pituitary tumor cells [5].

Psychiatry related information on Crhr1

• This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction [6].
• CRFR1 knockout mice displayed an increased exploratory behavior in both the Elevated Plus-maze (EPM) and the Black and White (B-W) test box models of anxiety, indicating an anxiolytic-like effect of the CRFR1 gene deletion [7].
• Corticosterone response to maternal deprivation was significantly increased in both CRHR1-deficient lines [8].
• The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919) [9].
• Disruption of feeding behavior in CRH receptor 1-deficient mice is dependent on glucocorticoids [10].

High impact information on Crhr1

• We propose that Crhr2 predominantly mediates a central anxiolytic response, opposing the general anxiogenic effect of Crh mediated by Crhr1 [11].
• Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1 [11].
• Here we show that in mice lacking Crhr1, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced [12].
• Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase [12].
• In contrast to Crhr1 null mutants, conditional mutants were hypersensitive to stress corticotropin and corticosterone levels remained significantly elevated after stress [13].

Chemical compound and disease context of Crhr1

• Owing to the important role of 5-HT in the pathophysiology of mood and anxiety disorders, the latter observation may contribute to the therapeutical efficacy of CRH-R1 antagonists in these illnesses [14].

Biological context of Crhr1

• Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues [15].
• The distinct time courses of CRF-receptor-induced hypophagia suggest that separate pathways act cooperatively to adjust food intake during challenges to homeostasis [1].
• These data strongly indicate that central CRF over-expression in the mouse brain is associated with down-regulation of CRF1 mRNA and up-regulation of CRF2 mRNA in a brain-structure-specific way [16].
• These data indicate that CRF1 receptors mediate ethanol enhancement of GABAergic synaptic transmission in the CeA, and they suggest a cellular mechanism underlying involvement of CRF in ethanol's behavioral and motivational effects [17].
• In contrast, gene expression in Nes-CRHR1 pups was strikingly similar to that in maternally deprived control pups [8].

Anatomical context of Crhr1

• The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery [15].
• To dissect the involvement of CRH receptor 1 (CRHR1) and CRHR2, we used conditional knockout mice in which Crhr1 is inactivated in the anterior forebrain and limbic structures [18].
• We also examined the impact of CRF1 receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal [6].
• In addition, we demonstrated that the mCRFR2alpha gene is increased in the hypothalamus of the CRFR1-null compared with wild type mice [19].
• 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 [20].

Associations of Crhr1 with chemical compounds

• Furthermore, testing paired-pulse paradigm revealed a GABA receptor-dependent decrease of paired-pulse ratio in Crhr1(-/-) [21].
• These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H [6].
• Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors [17].
• These data indicate that resting ACTH secretion in CRF-R1 -/- mice is in part attributable to AVP-dependent mechanisms [22].
• In the paraventricular nucleus, Cam-CRHR1 animals displayed enhanced CRH and decreased vasopressin expression levels [8].

Physical interactions of Crhr1

• Further, CRF has been shown to contribute to excitability of hippocampal neurons during embryonic development by binding to CRF-R1; depolarization induced excitability appears to be critical for cell survival [23].

Regulatory relationships of Crhr1

• A 7-day intracerebroventricular infusion of Ucn transiently suppressed ad libitum food intake equally in CRFR1-/- and wild-type mice [1].
• However, since the effect of 10 nM CRF was additive with that of 1 microM VIP, the CRF receptor was not the site at which high concentrations of VIP stimulated ACTH release [24].
• However, CRH receptor type 2 mRNA expression is not altered in adult mouse ventricular cardiomyocytes stimulated in vitro with TNFalpha or IL-1alpha [25].
• Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors [26].

Other interactions of Crhr1

• Basal plasma AVP concentrations were significantly elevated in Crhr1-/- mice [27].
• Ucn II is a specific ligand for the type 2 CRF receptor (CRFR) [20].
• By contrast, CRFR1-/- mice did not respond to Ucn 1.5 h after injection [1].
• In particular, the diagonal band of Broca (vertical and horizontal limbs) showed a high degree of co-localization of CRH-R1 immunoreactivity and choline acetyltransferase immunoreactivity (both limbs >90%) [28].
• All catecholaminergic structures studied displayed a pattern of CRH-R1 immunoreactivity strongly overlapping the pattern of tyrosine hydroxylase immunoreactivity [28].

Analytical, diagnostic and therapeutic context of Crhr1

• The messenger RNA encoding the mouse CRF-R1 was detected by RT-PCR in mouse Leydig cell preparations [29].
• Immobilization for 1 hr generated a stress response that included the induction of anxiety through septal CRFR2 and the subsequent enhancement of learning through hippocampal CRFR1 [30].
• In whole-cell recordings, both CRF and ethanol enhanced gamma-aminobutyric acid-mediated (GABAergic) neurotransmission in CeA neurons from wild-type and CRF2 receptor knockout mice, but not CRF1 receptor knockout mice [17].
• By single cell PCR, the authors show that microglia and astrocytes express mRNA for both CRH-R1 and CRH-R2 [2].
• Using CRFR1 null mutant mice, the present study examined the functional significance of this receptor in ambulation and feeding [31].

References