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Volume 272, Number 45, Issue of November 7, 1997 pp. 28301-28307
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Desensitization of Thyrotropin-releasing Hormone Receptor-mediated Responses Involves Multiple Steps

(Received for publication, May 22, 1997, and in revised form, August 19, 1997)

From the Department of Pharmacology and Physiology and the Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Desensitization and recovery of the inositol 1,4,5-trisphosphate (IP₃) and intracellular free calcium concentration ([Ca²⁺]_i) responses to thyrotropin-releasing hormone (TRH) were measured in HEK293 cells stably expressing the G protein-coupled TRH receptor. TRH caused a large, rapid, and transient increase in IP₃ and a biphasic increase in [Ca²⁺]_i. Desensitization of the TRH response was measured by exposing cells to TRH, washing, and then incubating the cells in hormone-free medium before reintroducing TRH and measuring IP₃, [Ca²⁺]_i, and intracellular Ca²⁺ pool size. When cells were incubated with 1 µM TRH for 10 s or 10 min and reexposed to TRH, there was almost no IP₃ or [Ca²⁺]_i increase. The IP₃ response recovered first, followed by the [Ca²⁺]_i response. The ionomycin-releasable intracellular Ca²⁺ pool was almost completely depleted by TRH, and pool refilling was slow. Thrombin, endothelin, and carbachol, when combined, stimulated large increases in IP₃ and [Ca²⁺]_i, but did not block the IP₃ or [Ca²⁺]_i responses to TRH measured 10 min later. In contrast, cells exposed to TRH first responded to combined agonists with a nearly normal increase in IP₃, but no rise in [Ca²⁺]_i. Thus, the IP₃ response to TRH displays homologous desensitization, whereas the [Ca²⁺]_i response displays heterologous desensitization because depletion of intracellular Ca²⁺ pools prevents responses to other hormones.

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