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J Biol Chem, Vol. 274, Issue 34, 23901-23909, August 20, 1999

Multiple Protein Kinase Pathways Are Involved in Gastrin-releasing Peptide Receptor-regulated Secretion

Mark R. Hellmich, Kirk L. Ives, Vidyavathi Udupi, Melvyn S. Soloff^¶, George H. Greeley Jr., Burgess N. Christensen, and Courtney M. Townsend Jr.

From the Departments of  Surgery,  Physiology and Biophysics, and ^¶ Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555

Gastrin-releasing peptide (GRP) and its amphibian homolog, bombesin, are potent secretogogues in mammals. We determined the roles of intracellular free Ca²⁺ ([Ca²⁺]_i), protein kinase C (PKC), and mitogen-activated protein kinases (MAPK) in GRP receptor (GRP-R)-regulated secretion. Bombesin induced either [Ca²⁺]_i oscillations or a biphasic elevation in [Ca²⁺]_i. The biphasic response was associated with peptide secretion. Receptor-activated secretion was blocked by removal of extracellular Ca²⁺, by chelation of [Ca²⁺]_i, and by treatment with inhibitors of phospholipase C, conventional PKC isozymes, and MAPK kinase (MEK). Agonist-induced increases in [Ca²⁺]_i were also inhibited by dominant negative MEK-1 and the MEK inhibitor, PD89059, but not by an inhibitor of PKC. Direct activation of PKC by a phorbol ester activated MAPK and stimulated peptide secretion without a concomitant increase in [Ca²⁺]_i. Inhibition of MEK blocked both bombesin- and phorbol 12-myristate 13-acetate-induced secretion. GRP-R-regulated secretion is initiated by an increase in [Ca²⁺]_i; however, elevated [Ca²⁺]_i is insufficient to stimulate secretion in the absence of activation of PKC and the downstream MEK/MAPK pathways. We demonstrated that the activity of MEK is important for maintaining elevated [Ca²⁺]_i levels induced by GRP-R activation, suggesting that MEK may affect receptor-regulated secretion by modulating the activity of Ca²⁺-sensitive PKC.

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