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cis-Unsaturated Free Fatty Acids Block Growth Hormone and Prolactin Secretion in Thyrotropin-Releasing Hormone-Stimulated GH₃ Cells by Perturbing the Function of Plasma Membrane Integral Proteins¹

Cellular Endocrinology Laboratory, Department of Medicine, Compostela University School of Medicine and Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: Dr. F. F. Casanueva, P.O. Box 563, 15780 Santiago de Compostela, Spain. E-mail: meffcasa{at}uscmail.usc.es

In vivo FFA block basal and stimulated GH secretion and have been implicated in the pathogenesis of the altered GH secretion present in obesity and Cushing’s syndrome. Although a direct action on the somatotroph cell has been postulated, the FFA mechanism of action is unknown. The main biological target for FFA action is the cellular membrane, and it has been shown that these metabolites can block the activity of a number of plasma membrane pumps, channels, and receptor systems. In the present work, it was observed using different types of pituitary cells (GH₃, GH₄C₁, and rat pituitary primary cultures) that cis-unsaturated fatty acids, such as oleic, 1) do not perturb TRH binding or the homologous desensitization of the TRH receptor; 2) inhibit TRH-induced inositol 1,4,5-trisphosphate/diacylglycerol generation, probably by a direct perturbation of phospholipase C; 3) reduce the TRH-induced intracellular Ca²⁺ redistribution and the ensuing changes in membrane potential; 4) completely inhibit the [Ca²⁺]_i rise due to the TRH-induced opening of voltage-gated Ca²⁺ channels; and 5) abolish the TRH-induced Ca²⁺ efflux through plasma membrane Ca²⁺ pumps. These results suggest that cis-unsaturated FFA such as oleic acid selectively perturb the function of integral membrane proteins such as enzymes, channels, and pumps without perturbing the binding of ligands to receptors.

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