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Volume 272, Number 45, Issue of November 7, 1997 pp. 28308-28314
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Uncoupling of Calcium Mobilization and Entry Pathways in Endothelin-stimulated Pituitary Lactotrophs

(Received for publication, August 6, 1997, and in revised form, September 9, 1997)

From the Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

In cells expressing Ca²⁺-mobilizing receptors, InsP₃-induced Ca²⁺ release from intracellular stores is commonly associated with extracellular Ca²⁺ influx. Operation of these two Ca²⁺ signaling pathways mediates thyrotropin-releasing hormone (TRH) and angiotensin II (AII)-induced prolactin secretion from rat pituitary lactotrophs. After an initial hyperpolarization induced by Ca²⁺ mobilization from the endoplasmic reticulum (ER), these agonists generated an increase in the steady-state firing of action potentials, further facilitating extracellular Ca²⁺ influx and prolactin release. Like TRH and AII, endothelin-1 (ET-1) also induced a rapid release of Ca²⁺ from the ER and a concomitant spike prolactin secretion during the first 3-5 min of stimulation. However, unlike TRH and AII actions, Ca²⁺ mobilization was not coupled to Ca²⁺ influx during sustained ET-1 stimulation, as ET-1 induced a long-lasting abolition of action potential firing. This lead to a depletion of the ER Ca²⁺ pool, a prolonged decrease in [Ca²⁺]_i, and sustained inhibition of prolactin release. ET-1-induced inhibition and TRH/AII-induced stimulation of Ca²⁺ influx and hormone secretion were reduced in the presence of the L-type Ca²⁺ channel blocker, nifedipine. Basal [Ca²⁺]_i and prolactin release were also reduced in the presence of nifedipine. Furthermore, TRH-induced Ca²⁺ influx and secretion were abolished by ET-1, as TRH was unable to reactivate Ca²⁺ influx and prolactin release in ET-1-stimulated cells. Depolarization of the cells during sustained inhibitory action of ET-1, however, increased [Ca²⁺]_i and prolactin release. These results indicate that L-type Ca²⁺ channel represents a common Ca²⁺ influx pathway that controls basal [Ca²⁺]_i and secretion and is regulated by TRH/AII and ET-1 in an opposite manner. Thus, the receptor-mediated uncoupling of Ca²⁺ entry from Ca²⁺ mobilization provides an effective control mechanism in terminating the stimulatory action of ET-1. Moreover, it makes electrically active lactotrophs quiescent and unresponsive to other calcium-mobilizing agonists.

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