Targeted disruption of the Lasp-1 gene is linked to increases in histamine-stimulated gastric HCl secretion.
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).
Chew
Catherine S
CS
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912-3175, USA. cchew@mcg.edu
Chen
Xunsheng
X
Bollag
Roni J
RJ
Isales
Carlos
C
Ding
Ke Hong
KH
Zhang
Han
H
D000375:Aging; D000818:Animals; D003598:Cytoskeletal Proteins; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017353:Gene Deletion; D006632:Histamine / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism
D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C490692:Lasp1 protein, mouse; D009363:Neoplasm Proteins; D006632:Histamine