Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 29, Pages 19437-19444Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.006098
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Funding
- National Institutes of Health Grants [R01-DK26523, R01-DK61765, PO1-DK72084, R24-DK64388]
- The Hopkins Center for Epithelial Disorders Grants [T32-DK07632, K01-DK080930]
- Searle Young Investigators award
- Pennsylvania State University
- Huck Life Science Institute Center for Computational Proteomics
- Pennsylvania Department of Health using Tobacco Settlement Funds
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0843282] Funding Source: National Science Foundation
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Multiple studies suggest that phospholipase C-gamma(PLC-gamma) contributes to regulation of sodium/hydrogen exchanger 3 (NHE3) in the small intestine, although the mechanism(s) for this regulation remain unknown. We demonstrate here that PLC-gamma binds directly to the C terminus of NHE3 and exists in similar sized multiprotein complexes as NHE3. This binding is dynamic and decreases with elevated [Ca2+](i). The PLC-gamma-binding site in NHE3 was identified (amino acids 586-605) and shown to be a critical regulatory domain for protein complex formation, because when it is mutated, NHE3 binding to PLC-gamma as well as NHERF2 is lost. An inhibitory peptide, which binds to the Src homology 2 domains contained in PLC-gamma without interrupting binding of PLC-gamma to NHE3, was used to probe a non-lipase-dependent role of PLC-gamma. In the presence of this peptide, carbachol-stimulated calcium inhibition of NHE3 was lost. These results mirror previous studies with the transient receptor potential channel and suggest that PLC-gamma may play a common role in regulating the cell-surface expression of ion transporters.
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