HeterozygousgspMutation Renders Ion Channels of Human Somatotroph Adenoma Cells Unresponsive to Growth Hormone-Releasing Hormone¹

Abstract

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 alpha 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.

65 YEARS OF THE DOUBLE HELIX: Endocrine tumour syndromes in children and adolescents

“…The incidence of pituitary gigantism and acromegaly are approximately 8 and 11 cases per million person-years, respectively (Burton et al 2016). The cyclic AMP pathway is frequently dysregulated in sporadic somatotropinomas; somatic activating mutations in GNAS, which encodes for Gsa, are found in the heterozygous state (Yasufuku-Takano et al 1999), and on the maternal allele (Hayward et al 2001), representing the first and largest somatic genetic alteration in somatotropinomas (Landis et al 1989). Most cases of paediatric gigantism are familial.…”