Intracellular signal transduction during gastrin-induced histamine secretion in rat gastric ECL cells.

Activation of G(q) protein-coupled receptors usually causes a biphasic increase in intracellular calcium concentration ([Ca(2+)](i)) that is crucial for secretion in nonexcitable cells. In gastric enterochromaffin-like (ECL) cells, stimulation with gastrin leads to a prompt biphasic calcium response followed by histamine secretion. This study investigates the underlying signaling events in this neuroendocrine cell type. In ECL cells, RT-PCR suggested the presence of inositol 1,4,5-trisphosphate receptor (IP(3)R) subtypes 1-3. The IP(3)R antagonist 2-aminoethoxydiphenyl borate abolished both gastrin-induced elevation of [Ca(2+)](i) and histamine release. Thapsigargin increased [Ca(2+)](i), however, without inducing histamine secretion. In thapsigargin-pretreated cells, gastrin increased [Ca(2+)](i) through calcium influx across the plasma membrane. Both nimodipine and SKF-96365 inhibited gastrin-induced histamine release. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate induced histamine secretion, an effect that was prevented by nimodipine. In summary, gastrin-stimulated histamine release depends on IP(3)R activation and plasmalemmal calcium entry. Gastrin-induced calcium influx was mediated by dihydropyridine-sensitive calcium channels that appear to be L-type channels activated through a pathway involving activation of PKC.