Targeted disruption of the Lasp-1 gene is linked to increases in histamine-stimulated gastric HCl secretion

Catherine S. Chew, Xunsheng Chen, Roni J. Bollag, Carlos Isales, Ke Hong Ding, Han Zhang

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Lasp-1 (LIM and SH3 domain protein 1) is a multidomain actin-binding protein that is differentially expressed within epithelial tissues and brain. In the gastric mucosa, Lasp-1 is highly expressed in the HCl-secreting parietal cell, where it is prominently localized within the F-actin-rich subcellular regions. Histamine-induced elevation of parietal cell [cAMP]i increases Lasp-1 phosphorylation, which is correlated with activation of HCl secretion. To determine whether Lasp-1 is involved in the regulation of HCl secretion in vivo, we generated a murine model with a targeted disruption of the Lasp-1 gene. Lasp-1-null mice had slightly lower body weights but developed normally and had no overt phenotypic abnormalities. Basal HCl secretion was unaffected by loss of Lasp-1, but histamine stimulation induced a more robust acid secretory response in Lasp-1-null mice compared with wild-type littermates. A similar effect of histamine was observed in isolated gastric glands on the basis of measurements of accumulation of the weak base [14C] aminopyrine. In addition, inhibition of the acid secretory response to histamine by H2 receptor blockade with ranitidine proceeded more slowly in glands from Lasp-1-null mice. These findings support the conclusion that Lasp-1 is involved in the regulation of parietal HCl secretion. We speculate that cAMP-dependent phosphorylation of Lasp-1 alters interactions with F-actin and/or endocytic proteins that interact with Lasp-1, thereby regulating the trafficking/ activation of the H+, K+-ATPase (proton pump).

Original languageEnglish (US)
Pages (from-to)G37-G44
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume295
Issue number1
DOIs
StatePublished - Jul 2008

Keywords

  • Bone mineral density
  • LIM and SH3 domain protein
  • Transmission electron microscopy
  • [ C]aminopyrine

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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