The Experts below are selected from a list of 69 Experts worldwide ranked by ideXlab platform
Robert J. Isfort - One of the best experts on this subject based on the ideXlab platform.
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Urocortin II treatment reduces skeletal muscle mass and function loss during atrophy and increases nonatrophying skeletal muscle mass and function.
Endocrinology, 2003Co-Authors: Richard T. Hinkle, Elizabeth Donnelly, David B. Cody, Mary Beth Bauer, Robert J. IsfortAbstract:Two corticotropin-releasing factor 2 receptor (CRF2R)-selective peptides have been recently described, Urocortin II (also known as stresscopin-related peptide) and Urocortin III (stresscopin). We have used Urocortin II to evaluate the effects of activation of the CRF2R on skeletal muscle-related physiological processes. Administration of Urocortin II to mice prevented the loss of skeletal muscle mass resulting from disuse due to casting, corticosteroid treatment, and nerve damage. In addition, Urocortin II treatment prevented the loss of skeletal muscle force and myocyte cross-sectional area that accompanied muscle mass losses resulting from disuse due to casting. Finally, we observed increased skeletal muscle mass and force in normal muscles when mice are treated with Urocortin II. These results were confirmed using two additional CRF2R agonists, Urocortin I and sauvagine. Thus, activation of the CRF2R modulates skeletal muscle mass in both normal and atrophying muscle. Therefore, CRF2R-selective agonists may find utility in the treatment of skeletal muscle wasting diseases including age-related muscle loss or sarcopenia.
Charles Chavkin - One of the best experts on this subject based on the ideXlab platform.
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CRF1-R Activation of the Dynorphin/Kappa Opioid System in the Mouse Basolateral Amygdala Mediates Anxiety-Like Behavior
2013Co-Authors: Michael R. Bruchas, Benjamin B. L, Julia C. Lemos, Charles ChavkinAbstract:Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF1-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF1-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF2-R agonist Urocortin III did not affect open arm time, and mice lacking CRF2-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF2-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF1-R activation may mediate anxiety and CRF2-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF1-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injectioninduce
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crf1 r activation of the dynorphin kappa opioid system in the mouse basolateral amygdala mediates anxiety like behavior
PLOS ONE, 2009Co-Authors: Michael R. Bruchas, Julia C. Lemos, Benjamin B Land, Charles ChavkinAbstract:Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF1-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF1-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF2-R agonist Urocortin III did not affect open arm time, and mice lacking CRF2-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF2-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF1-R activation may mediate anxiety and CRF2-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF1-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injection-induced anxiety was mediated by dynorphin release in the BLA, local injection of norBNI blocked the stress or CRF-induced increase in anxiety-like behavior; whereas norBNI injection in a nearby thalamic nucleus did not. The intersection of stress-induced CRF and the dynorphin/KOR system in the BLA was surprising, and these results suggest that CRF and dynorphin/KOR systems may coordinate stress-induced anxiety behaviors and aversive behaviors via different mechanisms.
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the dysphoric component of stress is encoded by activation of the dynorphin κ opioid system
The Journal of Neuroscience, 2008Co-Authors: Benjamin B Land, Michael R. Bruchas, Julia C. Lemos, Erica J Melief, Charles ChavkinAbstract:Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a κ-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or Urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF2 receptor antagonist antisauvigine-30, but not by the CRF1 receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF2 receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes κ-receptor antagonists as promising therapeutics.
Florian Holsboer - One of the best experts on this subject based on the ideXlab platform.
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corticotropin releasing factor receptors 1 and 2 in anxiety and depression
Current Opinion in Pharmacology, 2002Co-Authors: J M H M Reul, Florian HolsboerAbstract:Abstract Corticotropin-releasing factor (CRF) and its related family members are implicated in stress-related disorders such as anxiety and depression. Recently, two new members of this neuropeptide family have been discovered in the brain: Urocortin II (also known as stresscopin-related peptide) and Urocortin III (also known as stresscopin). These Urocortins are selective agonists for the CRF 2 receptor, show a distinct neuroanatomical localization and are involved in stress-coping responses such as anxiolysis. Thus, CRF, the Urocortins and their receptors form an intricate network in the brain involved in the acute phase as well as the recovery phase of the stress response.
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On the role of corticotropin-releasing hormone receptors in anxiety and depression.
Dialogues in clinical neuroscience, 2002Co-Authors: J M H M Reul, Florian HolsboerAbstract:On the basis of extensive basic and clinical studies, corticotropin-releasing hormone (CRH) and its related family members are considered to play a pivotal role in stress-related disorders, such as anxiety and depression. CRH is regarded as the principal mediator in the brain of the stress response, as it mediates neuroendocrine, autonomic, and behavioral responses to stressful challenges. Recently, this neuropeptide family has expanded due to the discovery of two new members, Urocortin II (also termed stresscopin-related peptide) and Urocortin III (also termed stresscopin), which are selective agonists for the CRH receptor type 2. They show a discrete neuroanatomical localization and are involved in stress-coping responses, such as anxiolysis. Here, on the basis of recent developments, we suggest that CRH, the Urocortins, and their receptors form a complex system in the brain, which is recruited during both the acute and the recovery phases of the stress response.
Wolfgang H Fischer - One of the best experts on this subject based on the ideXlab platform.
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a soluble form of the first extracellular domain of mouse type 2β corticotropin releasing factor receptor reveals differential ligand specificity
Journal of Biological Chemistry, 2003Co-Authors: Marilyn H. Perrin, Jean Rivier, Michael R Digruccio, Steven C Koerber, Koichi S Kunitake, Deborah L Bain, Wolfgang H FischerAbstract:Abstract The heptahelical receptors for corticotropin-releasing factor (CRF), CRFR1 and CRFR2, display different specificities for CRF family ligands: CRF and Urocortin I bind to CRFR1 with high affinity, whereas Urocortin II and III bind to this receptor with very low affinities. In contrast, all the Urocortins bind with high affinities, and CRF binds with lower affinity to CRFR2. The first extracellular domain (ECD1) of CRFR1 is important for ligand recognition. Here, we characterize a bacterially expressed soluble protein, ECD1-CRFR2β, corresponding to the ECD1 of mouse CRFR2β. The K i values for binding to ECD1-CRFR2β are: astressin = 10.7 (5.4–21.1) nm, Urocortin I = 6.4 (4.7–8.7) nm, Urocortin II = 6.9 (5.8–8.3) nm, CRF = 97 (22–430) nm, Urocortin III = sauvagine >200 nm. These affinities are similar to those for binding to a chimeric receptor in which the ECD1 of CRFR2β replaces the ECD of the type 1B activin receptor (ALK4). The ECD1-CRFR2β possesses a disulfide arrangement identical to that of the ECD1 of CRFR1, namely Cys45–Cys70, Cys60–Cys103, and Cys84–Cys118. As determined by circular dichroism, ECD1-CRFR2β undergoes conformational changes upon binding astressin. These data reinforce the importance of the ECD1 of CRF receptors for ligand recognition and raise the interesting possibility that different ligands having similar affinity for the full-length receptor may, nevertheless, have different affinities for microdomains of the receptor.
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identification of Urocortin III an additional member of the corticotropin releasing factor crf family with high affinity for the crf2 receptor
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Kathy A Lewis, Marilyn H. Perrin, Teresa M. Reyes, Joan Vaughan, Jozsef Gulyas, Koichi S Kunitake, Chien Li, Amy L Blount, Cynthia J Donaldson, Wolfgang H FischerAbstract:The corticotropin-releasing factor (CRF) family of neuropeptides includes the mammalian peptides CRF, Urocortin, and Urocortin II, as well as piscine urotensin I and frog sauvagine. The mammalian peptides signal through two G protein-coupled receptor types to modulate endocrine, autonomic, and behavioral responses to stress, as well as a range of peripheral (cardiovascular, gastrointestinal, and immune) activities. The three previously known ligands are differentially distributed anatomically and have distinct specificities for the two major receptor types. Here we describe the characterization of an additional CRF-related peptide, Urocortin III, in the human and mouse. In searching the public human genome databases we found a partial expressed sequence tagged (EST) clone with significant sequence identity to mammalian and fish Urocortin-related peptides. By using primers based on the human EST sequence, a full-length human clone was isolated from genomic DNA that encodes a protein that includes a predicted putative 38-aa peptide structurally related to other known family members. With a human probe, we then cloned the mouse ortholog from a genomic library. Human and mouse Urocortin III share 90% identity in the 38-aa putative mature peptide. In the peptide coding region, both human and mouse Urocortin III are 76% identical to pufferfish Urocortin-related peptide and more distantly related to Urocortin II, CRF, and Urocortin from other mammalian species. Mouse Urocortin III mRNA expression is found in areas of the brain including the hypothalamus, amygdala, and brainstem, but is not evident in the cerebellum, pituitary, or cerebral cortex; it is also expressed peripherally in small intestine and skin. Urocortin III is selective for type 2 CRF receptors and thus represents another potential endogenous ligand for these receptors.
Marilyn H. Perrin - One of the best experts on this subject based on the ideXlab platform.
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Urocortin ii and Urocortin III are cardioprotective against ischemia reperfusion injury an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine heart
Endocrinology, 2004Co-Authors: Bhawanjit K. Brar, Marilyn H. Perrin, Alon Chen, Anne K. Jonassen, Elena M. Egorina, Alejandra Negro, Ole D. Mjøs, David S. Latchman, Kuo-fen LeeAbstract:Corticotropin-releasing factor (CRF) receptor type 2beta (CRFR2beta) is expressed in the heart. Urocortin (Ucn)-I activation of CRFR2beta is cardioprotective against ischemic reperfusion (I/R) injury by stimulation of the ERKs1/2 p42, 44. However, by binding CRF receptor type 1, Ucn-I can also activate the hypothalamic stress axis. Ucn-II/stresscopin related peptide and Ucn-III/stresscopin are two new members of the CRF/Ucn-I gene family and are selective for CRFR2beta. We propose that CRFR2beta selective Ucn-II or Ucn-III will protect cardiomyocytes and the ex vivo Langendorff perfused rat heart from I/R injury by activation of ERK1/2-p42, 44. Ucn-II is expressed in mouse cardiomyocytes, and Ucn-II or Ucn-III can bind to CRFR2beta, resulting in ERK1/2-p42, p-44 phosphorylation and cAMP stimulation. Phosphorylation of ERK1/2-p42, p-44 is regulated by the Ras/Raf-1 kinase pathway, independent of adenylate cyclase and, therefore, cAMP activation. Ucn-II and Ucn-III protect cardiomyocytes from I/R injury and reduce the percentage of infarct size:risk ratio in Langendorff perfused rat hearts exposed to regional I/R (P<0.001). The CRFR2 selective antagonist astressin2-B and an ERK1/2-p42, 44 inhibitor abolish the cardioprotective actions of Ucn-II and Ucn-III in reperfusion. Cardiomyocytes isolated from CRFR2-null mice are less resistant to I/R injury, compared with wild-type cardiomyocytes. 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. We emphasize an important endogenous cardioprotective role for CRFR2beta in the murine heart.
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a soluble form of the first extracellular domain of mouse type 2β corticotropin releasing factor receptor reveals differential ligand specificity
Journal of Biological Chemistry, 2003Co-Authors: Marilyn H. Perrin, Jean Rivier, Michael R Digruccio, Steven C Koerber, Koichi S Kunitake, Deborah L Bain, Wolfgang H FischerAbstract:Abstract The heptahelical receptors for corticotropin-releasing factor (CRF), CRFR1 and CRFR2, display different specificities for CRF family ligands: CRF and Urocortin I bind to CRFR1 with high affinity, whereas Urocortin II and III bind to this receptor with very low affinities. In contrast, all the Urocortins bind with high affinities, and CRF binds with lower affinity to CRFR2. The first extracellular domain (ECD1) of CRFR1 is important for ligand recognition. Here, we characterize a bacterially expressed soluble protein, ECD1-CRFR2β, corresponding to the ECD1 of mouse CRFR2β. The K i values for binding to ECD1-CRFR2β are: astressin = 10.7 (5.4–21.1) nm, Urocortin I = 6.4 (4.7–8.7) nm, Urocortin II = 6.9 (5.8–8.3) nm, CRF = 97 (22–430) nm, Urocortin III = sauvagine >200 nm. These affinities are similar to those for binding to a chimeric receptor in which the ECD1 of CRFR2β replaces the ECD of the type 1B activin receptor (ALK4). The ECD1-CRFR2β possesses a disulfide arrangement identical to that of the ECD1 of CRFR1, namely Cys45–Cys70, Cys60–Cys103, and Cys84–Cys118. As determined by circular dichroism, ECD1-CRFR2β undergoes conformational changes upon binding astressin. These data reinforce the importance of the ECD1 of CRF receptors for ligand recognition and raise the interesting possibility that different ligands having similar affinity for the full-length receptor may, nevertheless, have different affinities for microdomains of the receptor.
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identification of Urocortin III an additional member of the corticotropin releasing factor crf family with high affinity for the crf2 receptor
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Kathy A Lewis, Marilyn H. Perrin, Teresa M. Reyes, Joan Vaughan, Jozsef Gulyas, Koichi S Kunitake, Chien Li, Amy L Blount, Cynthia J Donaldson, Wolfgang H FischerAbstract:The corticotropin-releasing factor (CRF) family of neuropeptides includes the mammalian peptides CRF, Urocortin, and Urocortin II, as well as piscine urotensin I and frog sauvagine. The mammalian peptides signal through two G protein-coupled receptor types to modulate endocrine, autonomic, and behavioral responses to stress, as well as a range of peripheral (cardiovascular, gastrointestinal, and immune) activities. The three previously known ligands are differentially distributed anatomically and have distinct specificities for the two major receptor types. Here we describe the characterization of an additional CRF-related peptide, Urocortin III, in the human and mouse. In searching the public human genome databases we found a partial expressed sequence tagged (EST) clone with significant sequence identity to mammalian and fish Urocortin-related peptides. By using primers based on the human EST sequence, a full-length human clone was isolated from genomic DNA that encodes a protein that includes a predicted putative 38-aa peptide structurally related to other known family members. With a human probe, we then cloned the mouse ortholog from a genomic library. Human and mouse Urocortin III share 90% identity in the 38-aa putative mature peptide. In the peptide coding region, both human and mouse Urocortin III are 76% identical to pufferfish Urocortin-related peptide and more distantly related to Urocortin II, CRF, and Urocortin from other mammalian species. Mouse Urocortin III mRNA expression is found in areas of the brain including the hypothalamus, amygdala, and brainstem, but is not evident in the cerebellum, pituitary, or cerebral cortex; it is also expressed peripherally in small intestine and skin. Urocortin III is selective for type 2 CRF receptors and thus represents another potential endogenous ligand for these receptors.
