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Identification and Characterization of Multiple Corticotropin-Releasing Factor Type 2 Receptor Isoforms in the Rat Esophagus

Center for Ulcer Research and Education, Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Women’s Health (S.V.W., P.Y., L.W., Y.L.P., Y.T.), Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; Veterans Affairs Greater Los Angeles Healthcare System (S.V.W., Y.T.), Los Angeles, California 90073; and Division of Gastroenterology (C.-Y.C.), Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei 112, Taiwan

Address all correspondence and requests for reprints to: S. Vincent Wu, Ph.D., Center for Ulcer Research and Education, Building 115, Room 217, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: vwu{at}ucla.edu.

The rat esophagus shares some cellular features with skin squamous epithelium and striated muscle that express high levels of corticotropin-releasing factor type 2 (CRF₂) receptors or their cognate ligand urocortin (Ucn) 1, 2, and 3. We investigated the expression and cell signaling of CRF₂ receptors and ligands in the rat esophagus and lower esophageal sphincter (LES) by RT-PCR and quantitative PCR in normal and corticosterone-treated whole esophageal tissue, laser capture microdissected layers, and isolated esophageal cells. The expression of CRF₂ receptor protein and intracellular cAMP and ERK1/2 responses to CRF agonists and CRF₂ antagonist were determined in cultured esophageal cells and HEK-293 cells transfected with CRF_2b receptors. CRF₂ was abundantly expressed in the mucosa and longitudinal muscle layers of the esophagus and LES, whereas CRF₁ expression was scarce. CRF_2b wild-type transcript was predominantly expressed in the esophagus, and in addition, several new CRF₂ splice variants including six CRF_2a isoforms were identified. Expression of Ucn 1, Ucn 2, and to a smaller extent Ucn 3, but not CRF mRNA, was detected in the esophagus and LES. Ucn 1 and Ucn 2 stimulated dose-dependent cAMP production and ERK1/2 phosphorylation in the esophageal cells, whereas CRF and CRF₁ agonist, cortagine, had less potent effects. In addition, Ucn 2-stimulated cAMP and ERK responses were blocked by the CRF₂ antagonist, astressin₂-B. These data established the presence of a prominent CRF₂ signaling system in the esophagus and LES-encompassing multiple CRF₂ receptor variants and Ucn, suggesting a functional role in secretomotor activity and epithelial and muscle cell proliferation.

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