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Nucleotide Regulation of Growth Hormone-Releasing Factor Binding to Rat Pituitary Receptors^*

R. SCOTT STRUTHERS, MARILYN H. PERRIN and WYLIE VALE

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute La Jolla, California 92037
Division of Phamacology, Department of Medicine, M-013H, University of California-San Diego (R.S.S.,W. Y.) La Jolla, California 92093

Address requests for reprints to: Dr. Wylie Vale, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037.

Abstract

The specific binding of a GRF radioligand, [His¹,¹²⁵I-Tyr¹⁰,Nle²⁷]hGRF-l-32NH₂, to rat pituitary homogenates is reduced by the addition of GTP and its nonhydrolyzable analogs 5'-guanylylimidodiphosphate (GppNHp) and guanosine 5'-O-(3-thiotriphosphate) (GTP--S). GDP and cAMP had no effect while the nonhydrolyzable ATP analogs 5'-adenylylimidodiphosphate and adenosine 5'-O-(3-thiotriphosphate) did elicit a significant reduction in GRF binding. The effect of GppNHp was half-maximal at 0.2 µM, and the maximum inhibition achieved was 85%. The effect of 0.1 µM GppNHp on GRF competitive displacement experiments indicated a significant reduction in affinity for the ligand (K_d = 0.51 ± 0.11 nM in the absence of GppNHp and 2.1 ± 1.1 nM in its presence) without an effect on receptor number. The GRF radioligand dissociates slowly from its receptor (t. = 250 ± 50 min), but the addition of 0.1 fiU GppNHp converts approximately half of the receptors present to a more rapidly dissociating form (t_A = 9 ± 10 min). These results are consistent with existing models for receptor- G-protein interactions, and thus, we conclude that transduction of the GRF response across the cell membrane involves a guanine nucleotide-binding protein, presumably G₈. (Endocrinology 124: 24–29, 1989)

Footnotes

^* This work was supported in part by NIH Grant DK-26741, Sanofi, and The Harry and Grace Steele Foundation, and was conducted in part by The Clayton Foundation for Research, California Division.

Supported by the Paul Stock Foundation.

Clayton Foundation Senior Investigator.

Received July 11, 1988.

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