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Soluble Corticotropin-Releasing Hormone Receptor 2 Splice Variant Is Efficiently Translated But Not Trafficked for Secretion

Department of Biological Chemistry, Molecular and Behavioral Neuroscience Institute, The University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Audrey F. Seasholtz, University of Michigan, Molecular and Behavioral Neuroscience Institute, BSRB, Room 5035, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200. E-mail: aseashol{at}umich.edu.

CRH directs the physiological and behavioral responses to stress. Its activity is mediated by CRH receptors (CRH-R) 1 and 2 and modulated by the CRH-binding protein. Aberrant regulation of this system has been associated with anxiety disorders and major depression, demonstrating the importance of understanding the regulation of CRH activity. An mRNA splice variant of CRH-R2 (sCRH-R2) was recently identified that encodes the receptor’s ligand-binding extracellular domain but terminates before the transmembrane domains. It was therefore predicted to serve as a secreted decoy receptor, mimicking the ability of CRH-binding protein to sequester free CRH. Although the splice variant contains a premature termination codon, predicting its degradation by nonsense-mediated RNA decay, cycloheximide experiments and polysome profiles demonstrated that sCRH-R2 mRNA escaped this regulation and was efficiently translated. However, the resulting protein was unable to serve as a decoy receptor because it failed to traffic for secretion because of an ineffective signal peptide and was ultimately subjected to proteosomal degradation. Several other truncated splice variants of G protein-coupled transmembrane receptors regulate the amount of full-length receptor expression through dimerization and misrouting; however, receptor binding assays and immunofluorescence of cells cotransfected with sCRH-R2 and CRH-R2 or CRH-R1 indicated that sCRH-R2 protein does not alter trafficking or binding of full-length CRH-R. Although sCRH-R2 protein does not appear to function as an intracellular or extracellular decoy receptor, the regulated unproductive splicing of CRH-R2 pre-mRNA to sCRH-R2 may selectively alter the cellular levels of full-length CRH-R2 mRNA and hence functional CRH-R2 receptor levels.