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Intracellular Signaling Mechanisms Mediating Ghrelin-Stimulated Growth Hormone Release in Somatotropes

Department of Cell Biology, Physiology, and Immunology, University of Córdoba (M.M.M., R.M.L., E.R.-G., F.R.-P., S.G.-N., F.G.-N., J.P.C.), 14014 Córdoba, Spain; and Department of Medicine, Molecular Endocrinology Section (F.F.C.), University of Santiago de Compostela School of Medicine, 15705 Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: Dr. María M. Malagón, Department of Cell Biology, Edificio Severo Ochoa, Planta 3, Campus Universitario de Rabanales, University of Córdoba, E-14014 Córdoba, Spain. E-mail: bc1mapom{at}uco.es.

Ghrelin is a newly discovered peptide that binds the receptor for GH secretagogues (GHS-R). The presence of both ghrelin and GHS-Rs in the hypothalamic-pituitary system, together with the ability of ghrelin to increase GH release, suggests a hypophysiotropic role for this peptide. To ascertain the intracellular mechanisms mediating the action of ghrelin in somatotropes, we evaluated ghrelin-induced GH release from pig pituitary cells both under basal conditions and after specific blockade of key steps of cAMP-, inositol phosphate-, and Ca²⁺-dependent signaling routes. Ghrelin stimulated GH release at concentrations ranging from 10^-10 to 10^-6 M. Its effects were comparable with those exerted by GHRH or the GHS L-163,255. Combined treatment with ghrelin and GHRH or L-163,255 did not cause further increases in GH release, whereas somatostatin abolished the effect of ghrelin. Blockade of phospholipase C or protein kinase C inhibited ghrelin-induced GH secretion, suggesting a requisite role for this route in ghrelin action. Unexpectedly, inhibition of either adenylate cyclase or protein kinase A also suppressed ghrelin-induced GH release. In addition, ghrelin stimulated cAMP production and also had an additive effect with GHRH on cAMP accumulation. Ghrelin also increased free intracellular Ca²⁺ levels in somatotropes. Moreover, ghrelin-induced GH release was entirely dependent on extracellular Ca²⁺ influx through L-type voltage-sensitive channels. These results indicate that ghrelin exerts a direct stimulatory action on porcine GH release that is not additive with that of GHRH and requires the contribution of a multiple, complex set of interdependent intracellular signaling pathways.

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