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3',5'-Cyclic Adenosine Monophosphate Augments Intracellular Ca²⁺ Concentration and Gonadotropin-Releasing Hormone (GnRH) Release in Immortalized GnRH Neurons in an Na⁺-Dependent Manner

Department of Physiology, Nippon Medical School (K.K., Y.S., M.K.), Tokyo 113-8602, Japan; and Institute for Molecular and Cellular Regulation, Gunma University (H.K.), Maebashi 371-8511, Japan

Address all correspondence and requests for reprints to: Dr. Masakatsu Kato, Department of Physiology, Nippon Medical School, Sendagi 1, Bunkyo, Tokyo 113-8602, Japan. E-mail: mkato{at}nms.ac.jp.

In GT1-7 cells, cAMP increases the intracellular Ca²⁺ concentration ([Ca²⁺]_i) through activation of the voltage-gated Ca²⁺ channels, thereby facilitating GnRH release. To activate these channels, the membrane potential must be depolarized. In the present study we hypothesize that cAMP depolarizes the cells by increasing the membrane Na⁺ permeability, as in the case of somatotrophs and pancreatic ß-cells. To examine this, we analyzed [Ca²⁺]_i and [Na⁺]_i in GT1-7 cells by an intracellular ion-imaging technique along with cAMP assay by RIA.

Forskolin, a direct activator of adenylyl cyclase, increased [Ca²⁺]_i and [Na⁺]_i via cAMP formation. The forskolin-induced increase in [Ca²⁺]_i depended on the presence of Ca²⁺ and Na⁺ in the extracellular solution. This response was blocked by the voltage-gated Ca²⁺ channel blocker, nifedipine; the nonselective cation channel blocker, gadolinium (Gd³⁺); and the cyclic nucleotide-gated channel blocker, l-cis-diltiazem. In contrast, the forskolin-induced increase in [Na⁺]_i depended only on extracellular Na⁺, not on Ca²⁺. Gd³⁺ and l-cis-diltiazem also blocked the increase in [Na⁺]_i. Furthermore, the forskolin-induced increase in GnRH release was blunted in both low Ca²⁺ and low Na⁺ media. The results indicate that cAMP increases the membrane Na⁺ permeability, probably through nonselective cation channels on GT1-7 cells, thereby promoting GnRH release.

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