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MUCOSAL BIOLOGY

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

¹Institute of Molecular Medicine and Genetics, Departments of ²Medicine and ³Pathology, Medical College of Georgia, Augusta, Georgia; and ⁴Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China

Submitted 21 March 2008 ; accepted in final form 8 May 2008

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).

LIM and SH3 domain protein; transmission electron microscopy; [¹⁴C]aminopyrine; bone mineral density

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