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ENDOCRINE AND DIABETES

Differential Responses of Corticotropin-Releasing Hormone Receptor Type 1 Variants to Protein Kinase C Phosphorylation

Endocrinology and Metabolism, Division of Clinical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom (D.M., N.P., T.T., H.R., D.K.G.); Division of Pediatrics, The Children's Hospital of the Cleveland Clinic Foundation, Cleveland, Ohio (M.A.L.); and The Leeds Institute of Health, Genetics and Therapeutics, University of Leeds, Leeds, United Kingdom (E.W.H.)

Corticotropin-releasing hormone (CRH) regulates diverse biological functions in mammals, through activation of two types of specific G protein-coupled receptors that are expressed as multiple mRNA spliced variants. In most cells, the type 1 CRH receptor (CRH-R1) preferentially activates the G_s-adenylyl cyclase signaling cascade. CRH-R1-mediated signaling activity is impaired by insertion of 29 amino acids in the first intracellular loop, a sequence modification that is characteristic of the human-specific CRH-R1 variant. In various tissues, CRH signaling events are regulated by protein kinase C (PKC). The CRH receptors contain multiple putative PKC phosphorylation sites that represent potential targets. To investigate this, we expressed recombinant CRH-R1 or CRH-R1 in human embryonic kidney 293 cells and analyzed signaling events after PKC activation. Agonist (oxytocin) or phorbol 12-myristate 13-acetate-induced activation of PKC led to phosphorylation of both CRH-R1 variants. However, CRH-R1 and CRH-R1 exhibited different functional responses to PKC-induced phosphorylation, with only the CRH-R1 susceptible to cAMP signaling desensitization. This was associated with a significant decrease of accessible CRH-R1 receptors expressed on the cell surface. Both CRH-R1 variants were susceptible to homologous desensitization and internalization following treatment with CRH; however, PKC activation increased internalization of CRH-R1 but not CRH-R1 in a -arrestin-independent manner. Our findings indicate that CRH-R1 and -R1 exhibit differential responses to PKC-induced phosphorylation, and this might represent an important mechanism for functional regulation of CRH signaling in target cells.

Address correspondence to: Dr. Dimitris Grammatopoulos, Department of Biological Sciences, Sir Quinton Hazell Molecular Medicine Research Centre, The University of Warwick, Gibbet Hill Rd., Coventry CV4 7AL, UK. E-mail: d.grammatopoulos{at}warwick.ac.uk

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