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Joachim Spiess – 1st expert on this subject based on the ideXlab platform
Corticotropin-releasing factor receptor 1 and central heart rate regulation in mice during expression of conditioned fear.Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Oliver Stiedl, Olaf Jahn, Michael Meyer, Sven Ove Ögren, Joachim SpiessAbstract:
The present study was performed to 1) determine heart rate (HR) effects mediated through central corticotropin-releasing factor receptor subtypes 1 (CRF1) investigate and 2 (CRF2) and 2) to the contribution of endogenous CRF to baseline HR and its fear-induced adjustment in freely moving mice. CRF ligands were injected into both lateral ventricles (i.c.v.) 15 min before the presentation of a conditioned auditory fear stimulus (CS). Initial behavioral results suggest an ovine CRF (oCRF)-mediated enhanced baseline fear and mildly enhanced conditioned auditory fear. In contrast, i.c.v. injection of oCRF (35–210 ng/mouse) dose-dependently decreased baseline HR, increased HR variability, and attenuated the CS-induced tachycardia. This effect is suggested to depend on a combined activation of sympathetic and parasympathetic activity referred to as enhanced sympathovagal antagonism. An extreme bradycardia was elicited by oCRF injection into the lower brainstem. All HR effects were probably mediated by CRF1 because injection of the CRF2-selective agonist mouse urocortin II was ineffective, and the baseline bradycardia by i.c.v. CRF was preserved in CRF2-deficient mice. Injection of various CRF receptor antagonists including the CRF2-selective Antisauvagine–30 did not affect the conditioned HR response. This finding suggests that endogenous CRF does not contribute to the fear-mediated tachycardia. Thus, the hypothesis of an involvement of CRF in HR responses of mice to acute aversive stimulation is rejected. Pharmacological evidence points at the involvement of CRF1 in enhanced sympathovagal antagonism, a pathological state contributing to elevated cardiac risk, whereas the physiological role of the brain CRF system in cardiovascular regulation remains to be determined.
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.The Journal of Neuroscience, 2003Co-Authors: Farahnaz Sananbenesi, Joachim Spiess, Andre Fischer, Christina Schrick, Jelena RadulovicAbstract:
A coordinated activation of multiple interlinked signaling pathways involving cAMP-dependent protein kinase (PKA) and mitogen-activated extracellular signal-regulated kinases (Mek-1/2) regulates gene expression and neuronal changes underlying memory consolidation. In the present study we investigated whether these molecular cascades might mediate the effects of stress on memory formation. We also investigated the role of hippocampal corticotropin-releasing factor receptor 2 (CRF 2 ) in stress-enhanced learning and molecular signaling mediated by PKA, Mek-1/2, and their downstream targets extracellularly regulated kinases 1 and 2 (Erk-1/2) and p90-ribosomal-s-kinase-1 (p90Rsk-1). Acute 1 hr immobilization was used as a stressful stimulus, and one-trial context-dependent fear conditioning was used as a model for associative learning. Training of BALB/c mice 3 hr after the end of immobilization resulted in an enhancement of conditioned fear, as indicated by significantly increased freezing behavior of stressed when compared with nonstressed mice. Interestingly, Erk-1/2 phosphorylation after conditioning of nonstressed and stressed mice depended on PKA and Mek-1/2, respectively. Intrahippocampal injection of the selective Mek-1/2 inhibitor U0126 or CRF 2 antagonist Antisauvagine–30 (aSvg-30) prevented stress-enhanced fear conditioning and Mek-1/2-dependent activation of Erk-1/2 and p90Rsk-1. aSvg-30 did not affect the phosphorylation of the PKA regulatory subunit II of stressed mice. The molecular and behavioral effects of CRF 2 coincided with stress-induced upregulation of CRF 2 mRNA. These results suggest that modulation of Mek-1/2-dependent signaling by hippocampal CRF 2 can be selectively involved in the delayed effects of stress on memory consolidation.
Stress-mediated heart rate dynamics after deletion of the gene encoding corticotropin-releasing factor receptor 2.European Journal of Neuroscience, 2003Co-Authors: Oliver Stiedl, Michael G Rosenfeld, Michael Meyer, Toshimitsu Kishimoto, Joachim SpiessAbstract:
The objective of the present study was to investigate the potential role of corticotropin-releasing factor receptor subtype 2 (CRFR2) in autonomic regulation of heart rate and heart rate variability under physiological conditions in conscious mice. Heart rate dynamics during novelty exposure and auditory fear conditioning were assessed by radiotelemetry. 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. The heart rate responses during retention of conditioned auditory fear were similar and the exponential relationship between heart rate and heart rate variability was independent of genotype. Pharmacological stimulation of the peripheral CRFR2β by intraperitoneal injection of 200 ng human/rat corticotropin-releasing factor yielded a sustained tachycardia in wildtype control (CRFR2 + / + ) mice which was absent in CRFR2-deficient (CRFR2 – / – ) mice. Similarly, the tachycardia was effectively blocked by preinjection of the CRFR2 antagonist Antisauvagine–30. In conclusion, the results indicate the involvement of CRFR2 in heart rate dynamics upon pharmacological stimulation but demonstrate that CRFR2 is not involved in baseline heart rate regulation and stress-mediated modulation of heart rate responses.
Tamotsu Shibasaki – 2nd expert on this subject based on the ideXlab platform
Corticotropin-releasing factor (CRF) receptor subtypes in mediating neuronal activation of brain areas involved in responses to intracerebroventricular CRF and stress in rats.Peptides, 2011Co-Authors: Chiaki Takahashi, Hisayuki Ohata, Tamotsu ShibasakiAbstract:
Abstract Corticotropin-releasing factor (CRF) plays an important role in stress responses through activation of its receptor subtypes, CRF1 receptor (CRF 1 ) and CRF2 receptor (CRF 2 ). The parvocellular paraventricular nucleus of the hypothalamus (PVNp), the central nucleus of the amygdala (CeA), and the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), which are rich in CRF neurons with equivocal expression of CRF 1 and CRF 2 , are involved in stress-related responses. In these areas, Fos expression is induced by various stimuli, although the functions of CRF receptor subtypes in stimuli-induced Fos expression are unknown. To elucidate this issue and to examine whether Fos is expressed in CRF or non-CRF neurons in these areas, the effects of antalarmin and Antisauvagine–30 (AS-30), CRF 1 – and CRF 2 -specific antagonists, respectively, on intracerebroventricular (ICV) CRF- or 60 min-restraint-induced Fos expression were examined in rats. ICV CRF increased the number of Fos-positive CRF and non-CRF neurons in the PVNp, with the increases being inhibited by antalarmin in CRF and non-CRF neurons and by AS-30 in CRF neurons. Restraint also increased Fos-positive CRF and non-CRF neurons in the PVNp, with the increases being inhibited by antalarmin in the CRF neurons. ICV CRF also increased Fos-positive non-CRF neurons in the CeA and the BNSTov, which was inhibited by AS-30 in both areas, and inhibited by antalarmin in the BNSTov only. Restraint increased Fos-positive non-CRF neurons in the CeA and BNSTov, with the increases being almost completely inhibited by either antagonist. These results indicate that both ICV CRF and restraint activate both CRF and non-CRF neurons in the PVNp and non-CRF neurons in the CeA and BNSTov, and that the activation is mediated by CRF 1 and/or CRF 2 . However, the manner of involvement for CRF 1 and CRF 2 in ICV CRF- and restraint-induced activation of neurons differs with respect to the stimuli and brain areas; being roughly equivalent in the CeA and BNSTov, but different in the PVNp. Furthermore, the non-CRF 1&2 -mediated signals seem to primarily play a role in restraint-induced activation of non-CRF neurons in the PVNp since the activation was not inhibited by CRF receptor antagonists.
Involvement of CRF2 receptor in the brain regions in restraint-induced anorexia.Neuroreport, 2011Co-Authors: Hisayuki Ohata, Tamotsu ShibasakiAbstract:
We have reported that corticotropin-releasing factor (CRF) receptor subtypes, CRF 1 and CRF 2 , are involved in stress-induced anorexia. To clarify in which brain regions the CRF receptor is involved in mediating stress-induced anorexia, we examined the effect of microinjecting CRF 1 -selective or CRF 2 -selective antagonist into the lateral septum or the bed nucleus of the stria terminalis (BNST), which are implicated in regulating stress response. The results demonstrated that injecting Antisauvagine–30 into the lateral septum or the BNST significantly attenuated restraint-induced anorexia, whereas injecting antalarmin into these regions did not affect anorexia. These results suggest that the CRF 2 receptor in the lateral septum and the BNST is involved in the stress-induced inhibitory mechanism of feeding behavior.
Nicotine suppresses energy storage through activation of sympathetic outflow to brown adipose tissue via corticotropin-releasing factor type 1 receptor.Neuroscience Letters, 2009Co-Authors: Asuka Mano-otagiri, Hisayuki Ohata, Azusa Iwasaki-sekino, Keiko Arai, Tamotsu ShibasakiAbstract:
Abstract Nicotine is known to stimulate energy expenditure, although the precise mechanism is unclear. To clarify the involvement of corticotropin-releasing factor (CRF) in the mechanism by which nicotine increases energy expenditure, the effect of intraperitoneal injection of nicotine (0.1 or 0.5 mg/kg) on the release of noradrenaline (NA), a stimulator of thermogenesis, in brown adipose tissue (BAT) important for energy expenditure was examined in rats. We also examined the effects of CRF receptor subtype antagonists on the nicotine-induced change in BAT NA release. Nicotine significantly increased BAT NA release at a dose of 0.5 mg/kg, and the increase was completely blocked by antalarmin, a CRF type 1 receptor antagonist, but not by Antisauvagine–30, a CRF type 2 receptor antagonist. These results suggest that nicotine increases energy expenditure by activating BAT function, and that CRF type 1 receptors are involved in the mechanism by which nicotine affects energy balance.
Frank M Dautzenberg – 3rd expert on this subject based on the ideXlab platform
Different binding modes of amphibian and human corticotropin-releasing factor type 1 and type 2 receptors: evidence for evolutionary differences.Journal of Pharmacology and Experimental Therapeutics, 2020Co-Authors: Frank M Dautzenberg, Jacqueline Higelin, Gabrielle Py-lang, Christophe Fischer, Matthew B. Wright, Gerda HuberAbstract:
The binding characteristics of corticotropin-releasing factor (CRF) type 1 (CRF 1 ) and type 2 (CRF 2 ) receptors from human (hCRF 1 and hCRF 2α ) and Xenopus (xCRF 1 and xCRF 2 ) were compared using four different 125 I-labeled CRF analogs, the agonists 125 I-CRF and 125 I-sauvagine, and the antagonists 125 I-astressin ( 125 I-AST) and 125 I-Antisauvagine–30 ( 125 I-aSVG). The hCRF 2α and xCRF 2 receptors bound all four radioligands with different affinities, whereas hCRF 1 did not bind 125 I-aSVG, and xCRF 1 bound neither 125 I-sauvagine nor 125 I-aSVG. Competitive binding studies using unlabeled agonists and antagonists with hCRF 1 and hCRF 2α receptors revealed that most agonists exhibited higher affinity in displacing agonist radioligands compared with displacement of antagonist radioligands. Exceptions were the agonists human and rat urocortin, which displayed high-affinity binding in the presence of either 125 I-labeled agonist or antagonist ligands. In contrast, the affinities of antagonists were independent of the nature of the radioligand. We also found that, in contrast to the mammalian CRF receptors, the affinity of ligand binding to xCRF 1 and xCRF 2 receptors strongly depended on the nature of the radioligand used for competition. For xCRF 1 , competitors showed different rank order binding profiles with 125 I-CRF compared with 125 I-AST as the displaceable ligand. Similarly, binding of competitors to the xCRF 2 receptor showed markedly different profiles with 125 I-CRF as the competed ligand compared with the other radioligands. These data demonstrate that amphibian CRF receptors have distinctly different binding modes compared with their mammalian counterparts.
Secondary structure of Antisauvagine analogues is important for CRF receptor antagonism: development of antagonists with increased potency and receptor selectivityPeptides, 2002Co-Authors: Olaf Brauns, Simone Brauns, Marc Jenke, Bodo Zimmermann, Frank M DautzenbergAbstract:
Abstract Antisauvagine–30 (aSVG) is the only high-affinity antagonist for the corticotropin-releasing factor (CRF) type 2 (CRF 2 ) receptor. A structure–activity relationship study was performed to pinpoint residues conferring aSVG’s selectivity. The aSVG-analogues being N-terminally extended by one or two residues or containing the Ala 22 Arg 23 Ala 24 (ARA-motif) of CRF, were synthesized. Additionally, a lactam bridge between positions 29 and 32 was introduced. The modified peptides were analyzed for α-helicity properties, binding affinities and antagonistic potencies at the rat CRF 1 and mouse CRF 2B receptors. While N-terminal prolongation and replacement of d -Phe 11 by Tyr 11 increased the affinity for the CRF 2 receptor, the introduction of the ARA motif resulted in a loss of CRF 2 receptor selectivity. These data show that aSVG 10–40 analogues are more potent CRF 2 receptor antagonists than aSVG 11–40 peptides, while introduction of the ARA-motif or a cyclic constraint between residues 29 and 32 favors binding to the CRF 1 receptor.
The highly selective CRF2 receptor antagonist K41498 binds to presynaptic CRF2 receptors in rat brainBritish Journal of Pharmacology, 2002Co-Authors: Andrew J. Lawrence, Frank M Dautzenberg, Elena Krstew, Andreas RuhmannAbstract:
Novel analogues of Antisauvagine–30 (aSvg-30), a selective antagonist for CRF2 receptors, have been synthesized and characterized in vitro and in vivo.
The analogues were tested for their ability to compete for [125I-Tyr0]Svg binding and to inhibit Svg-stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF1 (hCRF1), hCRF2α and hCRF2β receptor. One analogue [D-Phe11, His12, Nle17]Svg(11-40), named K41498, showed high affinity binding to hCRF2α (Ki=0.66±0.03 nM) and hCRF2β (Ki=0.62±0.01 nM) but not the hCRF1 receptor (ki=425+50 nM) and decreased Svg-stimulated cAMP accumulation in hCRF2 expressing cells. In conscious Wistar-Kyoto rats, K41498 (1.84 μg, i.v.) antagonized the hypotensive response to systemic urocortin (1.4 μg, i.v.), but did not block the pressor response to centrally administered urocortin (2.35 μg, i.c.v.).
K41498 was subsequently radio-iodinated, and in autoradiographic studies, specific (sensitive to rat urocortin, astressin and aSvg30, but insensitive to antalarmin) binding of 125I-K41498 (100 pM) was detected in the heart and in selected brain regions including the nucleus tractus solitarius (NTS), spinal trigeminal nucleus, lateral septum and around the anterior and middle cerebral arteries.
Following unilateral nodose ganglionectomy, binding of 125I-K41498 was reduced by 65% in the ipsilateral NTS, indicative of presynaptic CRF2 receptors on vagal afferent terminals.
These data demonstrate that K41498 is a useful tool to study native CRF2 receptors in the brain and periphery.
British Journal of Pharmacology (2002) 136, 896–904. doi:10.1038/sj.bjp.0704783