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      Effect of Stress and Adrenalectomy on Urocortin II mRNA Expression in the Hypothalamic Paraventricular Nucleus of the Rat

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          Urocortin II (Ucn II) is a novel corticotropin-releasing hormone (CRH)-related peptide discovered as a selective agonist for type-2 CRH receptor. In the rat or mouse brain, Ucn II mRNA shows weak expression mainly in the hypothalamic paraventricular nucleus (PVN) and the locus coeruleus (LC). Understanding the regulation of Ucn II mRNA expression under varying conditions provides new insights into central stress response. We examined expression of Ucn II mRNA in the PVN and LC following immobilization stress, water deprivation, and adrenalectomy. Rats subjected to immobilization stress exhibited a dramatic induction of Ucn II mRNA expression in the parvocellular part of the PVN at the end of 2 h of immobilization. In contrast, water deprivation for 3 days induced Ucn II mRNA expression mainly in the magnocellular part of the PVN. Although water-deprived rats showed a marked decrease in their food intake, pair-fed rats failed to alter PVN Ucn II mRNA expression, suggesting that osmotic stimuli per se, but not reduced food consumption during water deprivation, caused Ucn II mRNA induction in the magnocellular part of the PVN. Adrenalectomized rats failed to show an increase in Ucn II mRNA in the PVN when compared to sham-operated rats. Double-label in situ hybridization revealed colocalization of Ucn II mRNA in approximately 45% of the CRH mRNA-expressing cells in the parvocellular part of the PVN following immobilization, or colocalization in most of the vasopressin mRNA-expressing cells in the magnocellular part of the PVN following water deprivation. In the LC, no induction of Ucn II mRNA was observed in any of the three experimental conditions, indicating that the regulation of Ucn II mRNA expression was site-specific. The results show a stressor-specific regulation of Ucn II mRNA expression in the PVN and raise the possibility that Ucn II mRNA plays a modulatory role in stress-induced alteration of anterior and posterior pituitary function, depending on the type of stress.

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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.

          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.
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            Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1.

            Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol. Two CRH receptors, Crhr1 and Crhr2, have been identified in the mouse. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase. 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. The homozygous mutants exhibit increased exploratory activity and reduced anxiety-related behaviour under both basal conditions and following alcohol withdrawal. Our results demonstrate a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behaviour.
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              Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors.

              Here we describe the cloning and initial characterization of a previously unidentified CRF-related neuropeptide, urocortin II (Ucn II). Searches of the public human genome database identified a region with significant sequence homology to the CRF neuropeptide family. By using homologous primers deduced from the human sequence, a mouse cDNA was isolated from whole brain poly(A)(+) RNA that encodes a predicted 38-aa peptide, structurally related to the other known mammalian family members, CRF and Ucn. Ucn II binds selectively to the type 2 CRF receptor (CRF-R2), with no appreciable activity on CRF-R1. Transcripts encoding Ucn II are expressed in discrete regions of the rodent central nervous system, including stress-related cell groups in the hypothalamus (paraventricular and arcuate nuclei) and brainstem (locus coeruleus). Central administration of 1-10 microg of peptide elicits activational responses (Fos induction) preferentially within a core circuitry subserving autonomic and neuroendocrine regulation, but whose overall pattern does not broadly mimic the CRF-R2 distribution. Behaviorally, central Ucn II attenuates nighttime feeding, with a time course distinct from that seen in response to CRF. In contrast to CRF, however, central Ucn II failed to increase gross motor activity. These findings identify Ucn II as a new member of the CRF family of neuropeptides, which is expressed centrally and binds selectively to CRF-R2. Initial functional studies are consistent with Ucn II involvement in central autonomic and appetitive control, but not in generalized behavioral activation.

                Author and article information

                S. Karger AG
                July 2003
                18 July 2003
                : 78
                : 1
                : 1-11
                Second Department of Internal Medicine, Kochi Medical School, Nankoku-city, Kochi, Japan
                71700 Neuroendocrinology 2003;78:1–11
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 8, Tables: 3, References: 38, Pages: 11
                Stress and Glucocorticoid Feedback


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