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J. Biol. Chem., Vol. 276, Issue 20, 16986-16991, May 18, 2001

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Arachidonic Acid Modulates the Spatiotemporal Characteristics of Agonist-evoked Ca²⁺ Waves in Mouse Pancreatic Acinar Cells^*

Gregor Siegel, Lutz Sternfeld, Antonio González, Irene Schulz, and Andreas Schmid^§

From the Department of Physiology II, University of Saarland, D-66421 Homburg/Saar, Germany

In pancreatic acinar cells analysis of the propagation speed of secretagogue-evoked Ca²⁺ waves can be used to examine coupling of hormone receptors to intracellular signal cascades that cause activation of protein kinase C or production of arachidonic acid (AA). In the present study we have investigated the role of cytosolic phospholipase A₂ (cPLA₂) and AA in acetylcholine (ACh)- and bombesin-induced Ca²⁺ signaling. Inhibition of cPLA₂ caused acceleration of ACh-induced Ca²⁺ waves, whereas bombesin-evoked Ca²⁺ waves were unaffected. When enzymatic metabolization of AA was prevented with the cyclooxygenase inhibitor indomethacin or the lipoxygenase inhibitor nordihydroguaiaretic acid, ACh-induced Ca²⁺ waves were slowed down. Agonist-induced activation of cPLA₂ involves mitogen-activated protein kinase (MAPK) activation. An increase in phosphorylation of p38^MAPK and p42/44^MAPK within 10 s after stimulation could be demonstrated for ACh but was absent for bombesin. Rapid phosphorylation of p38^MAPK and p42/44^MAPK could also be observed in the presence of cholecystokinin (CCK), which also causes activation of cPLA₂. ACh-and CCK-induced Ca²⁺ waves were slowed down when p38^MAPK was inhibited with SB 203580, whereas inhibition of p42/44^MAPK with PD 98059 caused acceleration of ACh- and CCK-induced Ca²⁺ waves. The spreading of bombesin-evoked Ca²⁺ waves was affected neither by PD 98059 nor by SB 203580. Our data indicate that in mouse pancreatic acinar cells both ACh and CCK receptors couple to the cPLA₂ pathway. cPLA₂ activation occurs within 1-2 s after hormone application and is promoted by p42/44^MAPK and inhibited by p38^MAPK. Furthermore, the data demonstrate that secondary (Ca²⁺-induced) Ca²⁺ release, which supports Ca²⁺ wave spreading, is inhibited by AA itself and not by a metabolite of AA.

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