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Human Urocortin II, a Selective Agonist for the Type 2 Corticotropin-Releasing
Factor Receptor, Decreases Feeding and Drinking in the Rat Corticotropin-releasing factor (CRF) has been hypothesized to modulate consummatory behavior through the Type 2 CRF (CRF(2)) receptor. However, behavioral functions subserved by the CRF(2) receptor remain poorly understood. Recently, human urocortin II (hUcn II), a selective CRF(2) receptor agonist, was identified. To study the effects of this neuropeptide on ingestive behavior, we examined the effects of centrally infused hUcn II (i.c.v. 0, 0.01, 0.1, 1.0, 10.0 &mgr;g) on the microstructure of nose-poke responding for food and water in nondeprived, male rats. Malaise-inducing properties of the peptide were monitored using conditioned taste aversion (CTA) testing. To identify potential sites of action, central induction of Fos protein expression was examined. hUcn II dose dependently reduced the quantity and duration of responding for food and water at doses lower (0.01-1.0 &mgr;g) than that forming a CTA (10 &mgr;g). Effects were most evident during hours 4 to 6 of the dark cycle. Meal pattern analysis showed that hUcn II potently (0.1 &mgr;g) increased the satiating value of food. Rats ate and drank smaller and shorter meals without changing meal frequency. Rats also ate more slowly. hUcn II induced Fos in regions involved in visceral sensory processing and autonomic/neuroendocrine regulation and resembling those activated by appetite suppressants. hUcn II is a promising neuropeptide for investigating the role of the CRF(2) receptor in ingestive behavior. Inoue K,et al. J Pharmacol Exp Ther 2003 Apr 1;305(1):385-393 Human urocortin II, a new CRF-related peptide, displays selective CRF(2)-mediated action on gastric transit in rats Human urocortin (hUcn) II is a new member of the corticotropin-releasing factor (CRF) family that selectively binds to the CRF(2) receptor. We investigated the CRF receptors involved in mediating the effects of hUcn II and human/rat CRF (h/rCRF) on gut transit. Gastric emptying, 4 h after a solid meal, and distal colonic transit (bead expulsion time) were monitored simultaneously in conscious rats. CRF antagonists were given subcutaneously 30 min before intravenous injection of peptides or partial restraint (for 90 min). hUcn II (3 or 10 microg/kg i.v.) inhibited gastric emptying (by 45% and 55%, respectively) and did not influence distal colonic transit. The CRF(2) peptide antagonist astressin(2)-B blocked hUcn II action. h/rCRF, rat Ucn, and restraint delayed gastric emptying while accelerating distal colonic transit. The gastric response to intravenous h/rCRF and restraint was blocked by the CRF(2) antagonist but not by the CRF(1) antagonist CP-154,526, whereas the colonic response was blocked only by CP-154,526. None of the CRF antagonists influenced postprandial gut transit. These data show that intravenous h/rCRF and restraint stress-induced delayed gastric emptying involve CRF(2) whereas stimulation of distal colonic transit involves CRF(1). The distinct profile of hUcn II, only on gastric transit, is linked to its CRF(2) selectivity. Million M, et al. Am J Physiol Gastrointest Liver Physiol 2002 Jan;282(1):G34-40 Differential actions of peripheral corticotropin-releasing factor (CRF), urocortin II, and urocortin III on gastric emptying and colonic transit in mice: role of CRF receptor subtypes 1 and 2 Peripheral CRF inhibits gastric emptying and stimulates colonic motor function in rats. We investigated the role of CRF(1) and CRF(2) receptors in i.p. CRF-induced alterations of gut transit in conscious mice using selective CRF(1) and CRF(2) ligands injected i.p. Gastric emptying 2 h after ingestion of a solid chow meal and colonic transit (time to expel a bead inserted into the distal colon) were determined simultaneously. Rat/human (r/h)CRF, which has CRF(1) > CRF(2) binding affinity, decreased distal colonic transit time at lower doses (6-12 microg/kg) than those inhibiting gastric emptying (20-60 microg/kg). Ovine CRF, a preferential CRF(1) receptor agonist (6-60 microg/kg), reduced significantly the colonic transit time without altering gastric emptying, whereas the selective CRF(2) receptor agonists mouse urocortin II (20-60 microg/kg) and urocortin III (120 microg/kg) inhibited significantly gastric emptying without modifying colonic transit. The CRF(1)/CRF(2) receptor antagonist, astressin (30-120 microg/kg), dose dependently prevented r/hCRF (20 microg/kg)-induced inhibition of gastric emptying and reduction of colonic transit time. The selective CRF(1) receptor antagonists, NBI-27914 (C(18)H(20)Cl(4)N(4)C(7)H(8)O(3)S) and CP-154,526 (butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]e thylamine) (5-30 mg/kg), dose dependently blocked r/hCRF action on the colon without influencing the gastric response, whereas the CRF(2) receptor antagonist, antisauvagine-30 (30-100 microg/kg), dose dependently abolished r/hCRF-induced delayed gastric emptying and had no effect on colonic response. These data show that i.p. r/hCRF-induced opposite actions on upper and lower gut transit in conscious mice are mediated by different CRF receptor subtypes: the activation of CRF(1) receptors stimulates colonic propulsive activity, whereas activation of CRF(2) receptors inhibits gastric emptying. Martinez V,et al. J Pharmacol Exp Ther 2002 May;301(2):611-7 Two Identified Endogenous Ligands for Type 2 CRF Receptor Indicated in Mediation of Anorexic and Vascular Responses following in the Stress. New CRF/Urocortin family members Human Stresscopin (SCP) and Stresscopin Related Peptide (SRP), two selectively natural ligands for CRFR2, enable to suppress food intake, delay gastric emptying and decrease heat-induced edema. The gene of SCP and SRP were expressed in central and diverse peripheral tissues. Because CRFR2 is believed to be important in the regulation of the recovery phase of the stress response, SCP and SRP might be important in protecting the organism from damage incurred by prolonged or excessive exposure to stress. Unlike CRF and Urocortin, SCP and SRP have minimal effects on ACTH release and the resultant elevations in glucocorticoids. Hsu, S.Y. & Hsueh, A.J.W. Nature Medicine, 7 605-611, 2001 |
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Urocortin III (Human) & Urocortin III (Mouse) An additional member of CRF family with high affinity for the CRFR2 Lewis, K. et al. Proc. Natl. Acad. Sci. USA 98, 7570-7575, 2001 (June 19) |
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1. Urocortin III (Human) is identical with Stresscopin (3-40)-NH2
(Human). 2. Urocortin II (Urocortin Related Peptide, URP) (Human) is identical with Stresscopin Related Peptide (6-43)-NH2 (Human). References: Lewis, K. et al. Proc. Natl. Acad. Sci. USA 98, 7570-7575, 2001 (June 19); Hsu, S.Y. & Hsueh, A.J.W. Nature Medicine, 7 605-611, 2001 Review by Jun Yang on June 21, 2001 |
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-containing
rat cardiac A7r5 cells; b, CRHR1-containing
human retinoblastoma Y79 cells; or 293T cells expressing c,
recombinant CRHR2
; d,
recombinant CRHR2
, CRH; 
,
SCP; ,
SRP;
, Takifugu stresscopin;
, urocortin. 
428 