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.

中文翻译：

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GPR4 通过 MtT/S 细胞的细胞外酸化参与增加的生长激素和催乳素表达

分泌激素的垂体腺瘤显示不受调节的激素分泌过多并导致垂体功能亢进。然而，不受调节的激素产生和分泌的机制尚未完全阐明。实体瘤显示细胞外 pH 值降低，部分原因是无氧糖酵解分泌乳酸。已知细胞外酸化影响激素分泌。然而，细胞外酸化是否以及如何影响不受调节的激素产生和分泌仍然未知。在本研究中，我们发现 GPR4 是一种质子感应 G 蛋白偶联受体，在 MtT/S 细胞（一种产生生长激素和催乳素的垂体肿瘤细胞系）中高度表达。当我们降低细胞外 pH 值时，细胞中生长激素和催乳素 mRNA 的表达增加。两种增加的表达都被 GPR4 拮抗剂部分抑制。我们还发现细胞外酸化增强了生长激素释放因子诱导的 MtT/S 细胞的生长激素分泌。这些结果表明 GPR4 可能在产生激素的垂体肿瘤的激素分泌过多中起作用。GPR4拮抗剂将是防止过度分泌的有用工具。