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Ceramide Enhances Growth Hormone (GH)-Releasing Hormone-Stimulated Cyclic Adenosine 3',5'-Monophosphate Accumulation but Inhibits GH Release in Rat Anterior Pituitary Cells¹

Departments of Physiology and Medicine (C.L.C.), Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

Address all correspondence and requests for reprints to: Dr. C. L. Chik, Department of Medicine, 7–26 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7. E-mail: cchik{at}ualberta.ca

In this study, the effect of ceramide on GH-releasing hormone (GHRH)-stimulated cAMP accumulation and GH release in rat anterior pituitary cells was investigated. C2-, C6-, and C8-ceramide were found to enhance GHRH-stimulated cAMP accumulation. In contrast, their effects on GHRH-stimulated GH release were inhibitory. Treatment with a glucosylceramide synthase inhibitor produced a similar enhancing effect on cAMP accumulation and an inhibitory effect on GH release. To identify the pathway through which ceramide mediated its effect, it was found that ceramide inhibited GH release stimulated by KCl, BayK 8644, and a GH-releasing peptide, but not that stimulated by ionomycin or an activator of protein kinase C. Direct measurement of intracellular Ca²⁺ revealed that C2-ceramide inhibited GHRH- and KCl-mediated increases in intracellular Ca²⁺, suggesting that ceramide probably inhibits GH release through inhibition of the L-type Ca²⁺ channels. As for its mechanism on cAMP accumulation, the enhancing effect of ceramide on GHRH-stimulated cAMP accumulation was abolished in the presence of a phosphodiesterase inhibitor, isobutylmethylxanthine, suggesting that ceramide enhances the cAMP response through inhibition of its metabolism. Taken together, our results suggest that ceramide plays an important role in the regulation of GHRH-stimulated responses in somatotrophs. By reducing GH secretion while enhancing cAMP accumulation, ceramide may promote the synthesis and storage of GH in rat anterior pituitary cells.

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