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Ceramide Inhibits L-Type Calcium Channel Currents in Rat Pinealocytes¹

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, 7–33 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7. E-mail: cchik{at}ualberta.ca

In rat pinealocytes, ceramide can inhibit the KCl- and BayK 8644-mediated potentiation of cAMP and cGMP accumulation, suggesting that the L-type Ca²⁺ channel is a target of ceramide action. This was examined in the present study using intracellular Ca²⁺ measurement and patch-clamp studies. In fura-2-loaded pinealocytes, C2- and C6-ceramide inhibited the Ca²⁺ increase caused by BayK 8644 and KCl, but not that caused by norepinephrine, suggesting an inhibitory effect of ceramide on the L-type Ca²⁺ channels. Patch-clamp analysis confirmed that C2- and C6-ceramide, but not C2-dihydroceramide (the inactive analog) inhibited the L-type Ca²⁺ channel current. Furthermore, treatments known to increase cellular ceramide levels, including a glucosylceramide synthase inhibitor and sphingomyelinase, also inhibited this current. The inhibitory effect of ceramide on the current was attenuated by lavendustin A, a tyrosine kinase inhibitor, but not by H7, a serine/threonine kinase inhibitor. The effect of ceramide was mimicked by interleukin-1ß, a cytokine highly expressed in the pineal that is known to activate the sphingomyelin pathway. These results indicate that the sphingomyelin pathway is another important signaling mechanism that regulates the L-type Ca²⁺ channel, and tyrosine kinase appears to be involved in the effect of ceramide.

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