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Restoration of Growth Hormone-Releasing Hormone (GHRH) Responsiveness in Pituitary GH3 Cells by Adenovirus-Directed Expression of the Human GHRH Receptor¹

Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: ljameson{at}northwestern.edu

GH-secreting GH3 cells lack GH-releasing hormone (GHRH) receptors. In this study we used adenoviral vectors to transfer the human GHRH receptor to GH3 cells in an effort to restore GHRH responsiveness. A replication-deficient recombinant adenovirus (AdGHRH-R) was designed to allow cytomegalovirus promoter-driven expression of the GHRH receptor messenger RNA. COS-7 cells and GH-producing GH3 cells infected with AdGHRH-R showed GHRH receptor expression on their membranes and exhibited specific GHRH binding. The addition of GHRH to GH3 cells infected with AdGHRH-R increased cAMP levels, induced cAMP response element-binding protein phosphorylation and restored GH secretory responsiveness. GHRH treatment also caused activation of mitogen-activated-protein kinase, induction of c-fos, stimulation of GH promotor activity, and increased cellular proliferation. These findings indicate that adenoviral vectors carrying human GHRH receptor are useful for in vitro studies of GHRH receptor biology and represent a first step toward the development of gene therapy for dwarfism caused by GHRH receptor mutations.

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