NMDA channel activation regulates Ca2+ permeation and gene transcription during histamine‐stimulated gastric acid secretion (904.5)

Abstract

Background: Histamine‐stimulated gastric acid secretion is accompanied by oscillations in intracellular Ca2+. The receptor mediating these oscillations and the function of this Ca2+ signal are unknown. We aimed to test the hypothesis that histamine stimulation activates N‐methyl‐D‐aspartate (NMDA) channel‐mediated Ca2+ influx and gene transcription in parietal cells. Methods: Cultured rat parietal cells were stimulated with histamine plus IBMX with or without NMDA channel antagonists. Intracellular Ca2+ was visualized by microscopy using fura‐2 or fluo‐3. Western blots and RNA‐Seq were used to evaluate CREB/ATF‐1 activation and gene transcription, respectively. Results: Histamine stimulation induced Ca2+ oscillations/permeation that were blocked by NMDA channel antagonists. CREB and ATF‐1 were activated by histamine stimulation and blocked by NMDA channel antagonists. Transcriptome analysis identified numerous up‐ and down‐regulated genes linked to histamine stimulation with a subset affected by NMDA channel blockade. The top network function attributed to NMDA channel‐mediated genes was cell death and survival. Most of the highly up‐regulated genes were CREB target genes. Conclusions: Histamine‐stimulated Ca2+ oscillations are regulated by NMDA channels. Our data show that this pool of intracellular Ca2+ transcriptionally regulates cell survival‐associated genes in parietal cells.