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Ca²⁺ Transients Induced by Thyrotropin-Releasing Hormone Rapidly Lose Their Ability to Cause Release of Prolactin

Department of Pharmacology, Yale University School of Medicine New Haven, Connecticut 06510

Address requests for reprints to: Dr. Greg J. Law, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510.

Abstract

To investigate the relationship of changes in cytosolic free calcium concentrations ([Ca²⁺]_c) caused by TRH to changes in PRL secretion, we simultaneously monitored PRL release and [Ca²⁺]_c, using the fluorescent Ca2+ indicator indo-1, in freshly isolated perifused cells from rat anterior pituitary glands. We found that a 30-sec pulse of 100 nM TRH triggered a transient spike of [Ca²⁺]_c, but prolonged PRL release for up to 30 min; continuous administration of TRH caused a sustained elevation in [Ca²⁺]_c, but the same pattern and amount of PRL release as that caused by the pulse of TRH. PRL secretion was refractory to further pulses of TRH given at 10-min intervals for 40 min, but did respond to a second pulse of TRH given 40 min after the first pulse with no intervening pulses. Pulses of TRH given every 10 min still triggered spikes of [Ca²⁺]_c of the same magnitude as the first pulse, indicating that the cause of the refractory state must occur at a postreceptor step that is after the mobilization of [Ca²⁺]_c. A 30-sec pulse of a high concentration of KCI caused a transient spike of [Ca²⁺]_c and transient, not prolonged, release. Additional pulses of KCI cause progressively less PRL release, although the magnitude of the spikes in [Ca²⁺]_c did not change.

We conclude that a pulse of TRH must induce a change other than a [Ca²⁺]_c spike to cause prolonged stimulation of PRL secretion, and that administration of continuous TRH or of frequent pulses maintains the cells in a refractory state in which they have no additional response to spikes of [Ca²⁺]_c of the same magnitude. Spikes in [Ca²⁺]_c alone will not cause prolonged secretion, but may contribute to developing the refractory state.

FOOTNOTES

This work was supported by James Hudson Brown-Alexander B. Coxe Fellowship (to G.J.L.), NIH Training Grant CA-09085 (to J.A.P.), and USPHS Grant HD-11487.

This work was presented in part at the 69th Annual Meeting of The Endocrine Society, Indianapolis, IN, June 1987.

Received for publication November 23, 1988. Revision received December 12, 1988. Accepted for publication December 14, 1988.

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