Involvement of GPR4 in increased <i>growth hormone</i> and <i>prolactin</i> expressions by extracellular acidification in MtT/S cells

Abstract

Hormone-secreting pituitary adenomas show unregulated hormonal hypersecretion and cause hyperpituitarism. However, the mechanism of the unregulated hormone production and secretion has not yet been fully elucidated. Solid tumors show reduced extracellular pH, partly due to lactate secretion from anaerobic glycolysis. It is known that extracellular acidification affects hormone secretion. However, whether and how the extracellular acidification influences the unregulated hormone production and secretion remain unknown. In the present study, we found that GPR4, a proton-sensing G protein-coupled receptor, was highly expressed in MtT/S cells, a growth hormone-producing and prolactin-producing pituitary tumor cell line. When we reduced the extracellular pH, growth hormone and prolactin mRNA expressions increased in the cells. Both increased expressions were partially suppressed by a GPR4 antagonist. We also found that extracellular acidification enhanced growth hormone-releasing factor-induced growth hormone secretion from MtT/S cells. These results suggest that GPR4 may play a role in hypersecretion of the hormone from hormone-producing pituitary tumors. A GPR4 antagonist will be a useful tool for preventing the hypersecretion.

Recent advances in acid sensing by G protein coupled receptors

“…GPR4 appears to be involved in hormone release from the anterior pituitary. Proton-mediated GPR4 activation in a pituitary cell line was shown to increased growth hormone and prolactin secretion [ 55 ], whilst a transcriptome analysis of gonadotropin releasing hormone (GnRH) neurons isolated from mice at different stages of their oestrous cycle showed a significant downregulation of GPR4 during the first half of the reproductive cycle [ 86 ]. These findings are intriguing since GnRH and prolactin have opposite effects on the release of luteinizing hormone from the anterior pituitary, which is essential for triggering ovulation in cyclic ovulators such as humans.…”