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Heterozygous gsp Mutation Renders Ion Channels of Human Somatotroph Adenoma Cells Unresponsive to Growth Hormone-Releasing Hormone¹

Fourth Department of Internal Medicine (J.Y.-T., K.T., T.T., S.F., N.Y., T.F.), University of Tokyo School of Medicine, Bunkyo-ku, Tokyo 112-8688; Department of Neurosurgery (A.T.), Nippon Medical School, Bunkyo-ku, Tokyo 113-8603, and Neurological Institute (K.T.), Tokyo Women’s Medical College, Shinjuku-ku, Tokyo 162-0054, Japan

Address all correspondence and requests for reprints to: Junko Yasufuku-Takano, M.D., Ph.D., Fourth Department of Internal Med-icine, University of Tokyo School of Medicine, 3–28-6 Mejirodai, Bunkyo-ku, Tokyo 112-8688, Japan. E-mail: jytakano-tky{at}umin.ac.jp

Ionic mechanisms play an important role in the regulation of hormone secretion. The GHRH-induced GH release by human GH-secreting cells is transmitted through protein kinase A (PKA), which activates nonselective cation current (NSCC) and induces membrane depolarization, intracellular Ca²⁺ increase, and GH secretion. To evaluate whether ionic mechanisms have pathophysiological significance in GH oversecretion of GH-secreting pituitary adenomas, we examined four adenomas with constitutively active Gs mutation (gsp mutation) and compared with three gsp-negative adenomas. In primary-cultured cells of gsp-positive adenomas, GHRH did not increase the NSCC under voltage-clamp experiments. Detailed examination showed that NSCC was maximally activated at the basal level and application of GHRH did not increase the current in these adenomas. Furthermore, by using single-cell RT-PCR method, we demonstrated for the first time at the single cell level that gsp mutation is heterozygous in GH-secreting pituitary adenomas. These indicate that heterozygous gsp mutation fully activates NSCC at the basal level, which may account for the GH oversecretion in gsp-positive GH-secreting pituitary adenomas.