Gonadotropin-releasing hormone initiates multiple signaling pathways in human GH-secreting adenomas

A. Lania, G. Mantovani, E. Ferrante, L. M. Zavanone, M. Locatelli, S. Corbetta, P. Beck-Peccoz, Anna Spada

Research output: Contribution to journalArticlepeer-review

Abstract

Abnormal GH responses to GnRH test, observed in about 15% of patients with acromegaly, have been reported exclusively in patients bearing tumors without gsp mutation. The absence of responsiveness to GnRH in gsp+ tumors was not predicted on the basis of the mechanism of GnRH action that mainly involves the activation of calcium and protein kinase C dependent pathways. The aim of the present study was to investigate in detail the transduction of GnRH signaling in these tumors. GH-secreting adenomas removed from patients in vivo responsive to GnRH test were studied. Tumor DNA was screened for Gsα and GnRH receptor gene sequences. Intracellular calcium ([Ca2+]i) and cAMP levels were measured in dispersed cells and adenylyl cyclase (AC) activity in membrane preparations. DNA analysis showed wild sequence of both Gsα and GnRH receptor genes. GnRH caused a significant increase in intracellular Ca2+ that was associated with a significant stimulation of cAMP accumulation. In these cells neither TRH nor GHRP-6 were effective in causing significant modifications of cAMP levels, despite their ability to increase [Ca2+]i. Finally, GnRH was able to directly stimulate AC from 11.1±3.3 pmol/mg prot/min to 26.9±5.4 (p2+]i and AC in GH-secreting adenomas removed from responsive patients. The ability of GnRH to signal through Gsα protein may account for the lack of GH responses to GnRH observed in acromegalic patients with tumors carrying gsp mutation.

Original languageEnglish
Pages (from-to)328-333
Number of pages6
JournalJournal of Endocrinological Investigation
Volume27
Issue number4
Publication statusPublished - Apr 2004

Keywords

  • Adenylate cyclase
  • cAMP
  • G protein
  • GnRH

ASJC Scopus subject areas

  • Endocrinology

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