Heterozygous gsp mutation renders ion channels of human somatotroph adenoma cells unresponsive to growth hormone-releasing hormone

Ionic mechanisms play an important role in the regulation of hormone secret ion. The GHRH-induced GH release by human GH-secreting cells is transmitted through protein kinase A (PKA), which activates nonselective cation curren t (NSCC) and induces membrane depolarization, intracellular Ca2+ increase, and GH secretion. To evaluate whether ionic mechanisms have pathophysiologi cal significance in GH oversecretion of GH-secreting pituitary adenomas, we examined four adenomas with constitutively active Gsa mutation (gsp mutati on) and compared with three gsp-negative adenomas. Ln primary-cultured cell s of gsp-positive adenomas, GHRP did not increase the NSCC under voltage-cl amp experiments. Detailed examination showed that NSCC was maximally activa ted 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 dem onstrated for the first time at the single cell level that gsp mutation is heterozygous in GH-secreting pituitary adenomas. These indicate that hetero zygous gsp mutation fully activates NSCC at the basal level, which may acco unt for the GH oversecretion in gsp-positive GH-secreting pituitary adenoma s.