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Defective jejunal and colonic salt absorption and altered Na+/H+ exchanger 3 (NHE3) activity in NHE3 regulatory factor 1(NHERF1) adaptor protein deficient mice

Defective jejunal and colonic salt absorption and altered Na...

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2008北京国际生理科学学术大会

作者： BROERE N CINAR A SINGH A.K HILLESHEIM J BIEDERER B LNNEMANN M ROTTINGHAUS I krabbenhft a ENGELHARDT R RAUSCH B WEINMAN E.J DONOWITZ M HUBBARD A KOCHER O DE JONGE H.R HOGEMA B.M SEIDLER U Department of Biochemistry Erasmus University Medical Center3015GE Rotterdamthe Netherlands Department of Gastroenterology Hannover Medical SchoolHannover D-30625Germany Departments of Medicine and Physiology University of Maryland School of MedicineMaryland 21201 Departments of Medicine PhysiologyJohns Hopkins University School of MedicineBaltimoreMaryland21205-2195 Departement of Cell Biology Johns Hopkins University School of MedicineBaltimoreMaryland21205-2195 Department of Pathology Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMA 02215

We investigated the role of the Na/H exchanger 3(NHE3)regulatory factor 1(NHERFl)on intestinal salt and water absorption,brush border membrane morphology and on the NHE3 mRNA expression,protein abundance,and transport activity in the murine ***1-deficient mice displayed reduced jejunal fluid absorption in vivo,as well as a attenuated Na absorption in isolated mucosa of jejunal and colonic tissue but not of ileal mucosa in ***,cAMP-mediated inhibition of both parameters remained *** basal NHE3 transport rate was decreased in surface colonocytes,while inhibition by cAMP and cGMP was normal. Immunodetection of NHE3 revealed normal NHE3 localization in the brush border membrane(BBM)of NHERF1 null mice,but NHE3 abundance,as measured by Western blot,was significantly reduced in isolated membranes from the small and large ***,the microvilli in the proximal colon,but not in the small intestine, were significantly shorter in NHERF1 null *** knockout of PDZK1(NHERF3),another member of the NHERF family of adapter proteins,which binds to both NHE3 and NHERF1,further reduced basal NHE3 activity and caused complete loss of cAMP-mediated NHE3 *** activator of the exchange protein activated by cAMP(EPAC)had no effect on jejunal fluid absorption in vivo,but slightly inhibited NHE3 activity in surface colonocytes in *** conclusion,NHERF1 has segment-specific effects on intestinal salt absorption,NHE3 transport rates and NHE3 membrane abundance without affecting mRNA ***,unlike PDZK1,NHERF1 is not required for NHE3 regulation by cyclic nucleotides.

关键词： PDZ domain proteins intestinal electrolyte transport sodium absorption colon small intestine PDZK1 NHERF1 knockout mice

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