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 proteins

• Published in: Endocrinology (Philadelphia) 1997, Vol.138 (1), p.264-272
• Main Authors: PEREZ, F. R, CASABIELL, X, CAMINA, J. P, ZUGAZA, J. L, CASANUEVAZ, F. F
• Format: Article
• Language: English
• Subjects: Animals; Binding; Biological activity; Biological and medical sciences; Calcium (intracellular); Calcium - metabolism; Calcium channels; Calcium channels (voltage-gated); Calcium efflux; Calcium ions; Cell Line; Cell membranes; Cell physiology; Channel gating; Channels; Desensitization; Diglycerides; Efflux; Fatty acids; Fatty Acids, Nonesterified - pharmacology; Fatty Acids, Unsaturated - pharmacology; Fundamental and applied biological sciences. Psychology; Growth Hormone - secretion; Growth hormones; Inositol trisphosphate; Inositols; Membrane potential; Membrane proteins; Membrane Proteins - drug effects; Membranes; Metabolites; Molecular and cellular biology; Oleic acid; Pathogenesis; Phospholipase C; Pituitary; Pituitary Gland - cytology; Pituitary Gland - secretion; Prolactin; Prolactin - secretion; Proteins; Pumps; Rats; Receptor mechanisms; Receptors; Secretion; Signal transduction; Signal Transduction - drug effects; Thyroid-stimulating hormone; Thyrotropin-releasing hormone; Thyrotropin-Releasing Hormone - pharmacology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.138.1.4888

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.