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J. Biol. Chem., Vol. 280, Issue 29, 26896-26903, July 22, 2005

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Endothelin-induced, Long Lasting, and Ca²⁺ Influx-independent Blockade of Intrinsic Secretion in Pituitary Cells by G_z Subunits^*

Silvana A. Andric, Dragoslava Zivadinovic, Arturo E. Gonzalez-Iglesias, Agnieszka Lachowicz, Melanija Tomi, and Stanko S. Stojilkovic¶

From the Section on Cellular Signaling, Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-4510

The G protein-coupled receptors in excitable cells have prominent roles in controlling Ca²⁺-triggered secretion by modulating voltage-gated Ca²⁺ influx. In pituitary lactotrophs, spontaneous voltage-gated Ca²⁺ influx is sufficient to maintain prolactin release high. Here we show that endothelin in picomolar concentrations can interrupt such release for several hours downstream of spontaneous and high K⁺-stimulated voltage-gated Ca²⁺ influx. This action occurred through the G_z signaling pathway; the adenylyl cyclase-signaling cascade could mediate sustained inhibition of secretion, whereas rapid inhibition also occurred at elevated cAMP levels regardless of the status of phospholipase C, tyrosine kinases, and protein kinase C. In a nanomolar concentration range, endothelin also inhibited voltage-gated Ca²⁺ influx through the G_i/o signaling pathway. Thus, the coupling of seven-transmembrane domain endothelin receptors to G_z proteins provided a pathway that effectively blocked hormone secretion distal to Ca²⁺ entry, whereas the cross-coupling to G_i/o proteins reinforced such inhibition by simultaneously reducing the pacemaking activity.

Received for publication, February 28, 2005 , and in revised form, May 9, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Inst. of Biology and Ecology, University of Novi Sad, 2100 Novi Sad, Serbia.

Present address: Faculty of Postgraduate Studies, University of Lodz, 92-215 Lodz, Poland.

^¶ To whom correspondence should be addressed: Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bldg. 49, Rm. 6A-36, 49 Convent Dr., Bethesda, MD 20892-4510. Tel.: 301-496-1638; Fax: 301-594-7031; E-mail: stankos{at}helix.nih.gov.

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