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

Activation of G_qprotein-coupled receptors usually causes a biphasic increase inintracellular calcium concentration (Ca²⁺]_i)that is crucial for secretion in nonexcitable cells. In gastric enterochromaffin-like (ECL) cells, stimulation with gastrin leads to aprompt biphasic calcium response followed by histamine secretion. Thisstudy 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 (IP₃R) subtypes1-3. The IP₃R antagonist 2-aminoethoxydiphenyl borateabolished both gastrin-induced elevation ofCa²⁺]_i and histamine release. Thapsigarginincreased Ca²⁺]_i, however, without inducinghistamine secretion. In thapsigargin-pretreated cells, gastrinincreased Ca²⁺]_i through calcium influxacross the plasma membrane. Both nimodipine and SKF-96365 inhibitedgastrin-induced histamine release. The protein kinase C (PKC) activatorphorbol 12-myristate 13-acetate induced histamine secretion, an effectthat was prevented by nimodipine. In summary, gastrin-stimulatedhistamine release depends on IP₃R activation andplasmalemmal calcium entry. Gastrin-induced calcium influx wasmediated by dihydropyridine-sensitive calcium channels that appear tobe L-type channels activated through a pathway involving activation of PKC.