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Urocortin 3 (Ucn 3) is a corticotropin-releasing factor (CRF)-related peptide with high affinity for the type 2 CRF receptor (CRFR2). Central administration of Ucn 3 stimulates the hypothalamic-pituitary-adrenal axis, suppresses feeding, and elevates blood glucose levels, suggesting that activation of brain CRFR2 promotes stress-like responses. Several CRFR2-expressing brain areas, including the ventromedial hypothalamus (VMH) and the posterior amygdala (PA), may be potential sites mediating the effects of Ucn 3. In the present study, Ucn 3 or vehicle was bilaterally injected into the VMH or PA, and food intake and plasma levels of ACTH, corticosterone, glucose, and insulin were determined. Food intake was greatly reduced in rats following Ucn 3 injection into the VMH. Ucn 3 injection into the VMH rapidly elevated plasma levels of glucose and insulin but did not affect ACTH and corticosterone secretion. Injection of Ucn 3 into the PA did not alter any of the parameters measured. We determined that the majority of CRFR2-positive neurons in the VMH were excitatory glutamatergic, and a subset of these neurons project to the arcuate nucleus of the hypothalamus (ARH). Importantly, stimulation of CRFR2 in the VMH increased proopiomelanocortin mRNA expression in the ARH. In conclusion, the present study demonstrates that CRFR2 in the VMH mediates some of the central effects of Ucn 3, and the ARH melanocortin system may be a downstream target of VMH CRFR2 neurons. corticotrophin-releasing factor; urocortin; feeding; hypothalamus; blood glucose; hypothalamic-pituitary-adrenal axis doi: 10.1152/ajpendo.00402.2009

The crystal structure of the complete signaling complex formed between bone morphogenetic protein 2 (BMP-2) and the extracellular domains (ECDs) of its type I receptor [bone morphogenetic protein receptor type Ia (BMPR-Ia)-ECD] and its type II receptor [activin receptor type II (ActRII)-ECD] shows two fundamental structural constraints for receptor assembly. First, the homodimeric BMP-2 ligand assembles two pairs of each receptor symmetrically, where each of the receptor ECDs does not make physical contact. Therefore, conformational communication between receptor ECDs, if any, should be propagated through the central ligand. Second, the type I and II receptor interfaces of the complex, when compared with those of binary complexes such as BMP-2/BMPR Ia-ECD, BMP-7/ActRII-ECD, and activin/ActRIIb-ECD, respectively, show there are common sets of positions repeatedly used by both ligands and receptors. Therefore, specificity-determining amino acid differences at the receptor interfaces should also account for the disparity in affinity of individual receptors for different ligand subunits. We find that a specific mutation to BMP-2 increases its affinity to ActRII-ECD by 5-fold. These results together establish that the specific signaling output is largely determined by two variables, the ligand-receptor pair identity and the mode of cooperative assembly of relevant receptors governed by the ligand flexibility in a membrane-restricted manner. activin receptor | receptor assembly

The corticotropin-releasing factor (CRF) ligand family has diverse effects on the CNS, including the modulation of the stress response. The ligands' effects are mediated by binding to CRF G protein-coupled receptors. We have determined the 3D NMR structure of the N-terminal extracellular domain (EC[D.sub.1]) of the mouse CRF receptor 2[beta], which is the major ligand recognition domain, and identified its ligand binding site by chemical-shift perturbation experiments. The fold is identified as a short consensus repeat (SCR), a common protein interaction module. Mutagenesis reveals the integrity of the hormone-binding site in the full-length receptor. This study proposes that the EC[D.sub.1] captures the C-terminal segment of the ligand, whose N terminus then penetrates into the transmembrane region of the receptor to initiate signaling. Key residues of SCR in the EC[D.sub.1] are conserved in the G protein-coupled receptor subfamily, suggesting the SCR fold in all of the EC[D.sub.1s] of this subfamily.

Author(s): Jay Groppe [1, 2]; Jason Greenwald [1]; Ezra Wiater [3]; Joaquin Rodriguez-Leon [4]; Aris N. Economides [5]; Witek Kwiatkowski [1]; Markus Affolter [2]; Wylie W. Vale [3]; Juan Carlos [...]

Human urocortin II, a new CRF-related peptide, displays selective CR[F.sub.2]-mediated action on gastric transit in rats. Am J Physiol Gastrointest Liver Physiol 282: G34-G40, 2002. First published September 21, 2001; 10.1152/ajpgi.00283.2002.--Human urocortin (hUcn) II is a new member of the corticotropin-releasing factor (CRF) family that selectively binds to the CR[F.sub.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 [micro]g/kg iv) inhibited gastric emptying (by 45% and 55%, respectively) and did not influence distal colonic transit. The CR[F.sub.2] peptide antagonist [astressin.sub.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 CR[F.sub.2] antagonist but not by the CR[F.sub.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 CR[F.sub.2] whereas stimulation of distal colonic transit involves CR[F.sub.1]. The distinct profile of hUcn II, only on gastric transit, is linked to its CR[F.sub.2] selectivity. partial restraint; gastric emptying; distal colonic transit; CP-154,526; [astressin.sub.2]-B

Author(s): Kathy A. Lewis; Peter C. Gray; Amy L. Blount; Leigh A. MacConell; Ezra Wiater; Louise M. Bilezikjian; Wylie Vale (corresponding author) Activins and inhibins [1], structurally related members of [...]