Biochemical and Biophysical Research Communications, Vol.314, No.3, 916-924, 2004
Receptor-operated Ca2+ influx and its association with the Src family in secretagogue-stimulated pancreatic acini
We investigated signal transduction between receptor-operated Ca2+ influx (ROCI) and Src-related nonreceptor protein tyrosine kinase (PTK) in rat pancreatic acini. CCK and the Ca2+ ionophore enhanced the Src-related PTK activity, whereas the high-affinity CCK-A receptor agonists, fibroblast growth factor (FGF), and the protein kinase C (PKC) activator had no or little effect. This increase was abolished by eliminating [Ca2+](o) loading of the intracellular Ca2+ chelator, and administering the PTK inhibitor genistein. While genistein inhibited extracellular Ca2+ or Mn2+ entry induced by CCK and carbachol, it did not affect intracellular Ca2+ release and oscillations. CCK dose-dependently increased the Src phosphotransferase activity, which was abolished by inhibitors of G(q) protein, phospholipase C (PLC), and Src, but not by the calmodulin kinase (CaMK) inhibitor. Intensities of the Src band and amounts of tyrosine phosphorylated Src were enhanced by CCK stimulation. Thus, Src cascades appear to be coupled to the low-affinity CCK-A receptor and utilize G(q)-PLC pathways for their activation, independent of PKC and CaMKcascades. The low-affinity CCK-A receptor regulates ROCI via mediation of Src-related PTK and activates Src pathways to cause [Ca2+](o)-dependent pancreatic exocytosis. (C) 2003 Elsevier Inc. All rights reserved.