Disease relevance of Crhr2

• Both respond with increased edema formation in response to thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender [1].
• We propose the use of CRFR2 selective agonists, Ucn-II and Ucn-III, to treat ischemic heart disease because of their potent cardioprotective effects in the murine heart and their minimal impact on the hypothalamic stress axis [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].
• Similarly, the tachycardia was effectively blocked by preinjection of the CRFR2 antagonist antisauvagine-30 [4].
• Ethanol-induced conditioned taste aversion (CTA), loss of righting reflex (LORR), hypothermia, and ethanol metabolism kinetics were also examined in the CRF2 KO and WT mice [5].

Psychiatry related information on Crhr2

• We hypothesize that excessive CRF1 activation combined with reduced CRF2 signaling may contribute to information processing deficits seen in panic and posttraumatic stress disorder patients and support CRF1-specific pharmacotherapy [6].
• Heart rate responses and heart rate variability values were not different in CRFR2+/+ and CRFR2-/- mice during novelty exposure, which was associated with similar locomotor activity exhibited by both genotypes [4].

High impact information on Crhr2

• Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues [7].
• We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn [8].
• Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive [8].
• Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis [8].
• In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects [8].

Biological context of Crhr2

• The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2-/- mice [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 [9].
• They augment the effect of LPS by inducing Tlr4 gene expression, through CRF2, via activation of the transcription factors PU.1 and AP-1 [10].
• Mapping of the mouse corticotropin-releasing hormone receptor 2 gene (Crhr2) to chromosome 6 [11].
• In this work, we have used complimentary gene deletion and pharmacological approaches to elucidate the crucial role CRFR2 plays in the regulation of regional tissue thermogenesis and adaptive physiology [12].

Anatomical context of Crhr2

• The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery [7].
• Activation of the CRF 2 receptor modulates skeletal muscle mass under physiological and pathological conditions [13].
• Furthermore, a higher number of CRF2 mRNA-positive profiles are observed in the dorsal raphe nucleus (+32.2%) [9].
• 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 [14].
• Corticotropin-releasing factor receptor 2 (CRFR2) is found in both endothelial and smooth muscle cells (SMCs) in the vasculature, where its function has remained elusive [15].

Associations of Crhr2 with chemical compounds

• Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice [8].
• CRF1 (but not CRF2) receptor antagonists blocked both CRF and ethanol effects in wild-type mice [16].
• Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons [17].
• These data are consistent with the hypothesis that Ucn 2 functions as a local negative regulator of glucose uptake in skeletal muscle and encourage exploration of the possibility that suppression of the Ucn 2/CRFR2 pathway may provide benefits in insulin-resistant states such as type 2 diabetes [18].
• Following LPS injection to both female and male mice, CRH-R2 mRNA expression was decreased and UCN mRNA expression was increased in the atria and ventricle of both WT and CRH KO mice in each sex [19].

Regulatory relationships of Crhr2

• 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 [1].
• Urocortin 1 and Urocortin 2 induce macrophage apoptosis via CRFR2 [20].
• IL-1alpha and TNFalpha down-regulate CRH receptor-2 mRNA expression in the mouse heart [21].
• A centrally administered corticotropin-releasing factor type 2 receptor (CRFR2) antagonist blocked PFOS-induced anorexia [22].

Other interactions of Crhr2

• Corticotropin-releasing factor (CRF) receptor type 2beta (CRFR2beta) is expressed in the heart [2].
• These results provide evidence of the first specific roles for CRF-R2 and CRF-BP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for both drugs of abuse and stress [17].
• Echocardiography and cardiac catheterization were used in mice to assess the physiologic effects of i.v. UcnII and CRFR2 deficiency on left ventricular function and the systemic vasculature [23].
• Western blots show that cell cycle retinoblastoma protein, which is essential for cell cycle progression, is decreased by CRFR2 agonist treatment in SMCs [15].
• CRF-R2 was first observed in the initial axonal segments of some Purkinje cells at P5, and was evident in many Purkinje cell axon hillocks at P8 [24].

Analytical, diagnostic and therapeutic context of Crhr2

• By using RT-PCR and Southern hybridization, the relative mRNA expression levels of full-length (seven transmembrane domains) CRFR2alpha and the soluble form (sCRFR2alpha) in the mouse brain were measured with a single reaction [25].
• Urocortin (Ucn)-I activation of CRFR2beta is cardioprotective against ischemic reperfusion (I/R) injury by stimulation of the ERKs1/2 p42, 44 [2].
• By single cell PCR, the authors show that microglia and astrocytes express mRNA for both CRH-R1 and CRH-R2 [26].
• Further, by means of RT-PCR and in situ hybridization analyses, we could provide first evidence that both CRHR1 and CRHR2 are expressed in the mouse pituitary and adrenal cortex [27].
• In the present study, the postnatal (P) development (P0-P14) and cellular localization of CRF-R2 in different cell types was analyzed using PAP and double-label fluorescent immunohistochemistry; cell-specific antibodies were used to identify cells expressing CRF-R2 at different stages of postnatal development [24].

References