记笔记

Differential role for the PDZ proteins NHERF1,NHERF2 and PDZK1 in the regulation of CFTR-mediated intestinal anion secretion in vivo

SINGH Anurag Kumar¹RIEDERER Brigitte¹KRABBENHfT Anja¹RAUSCH Brigitte¹DE JONGE Hugo R²DONOWITZ Mark³WEINMAN Edward J⁴KOCHER Olivier⁵HOGEMA Boris M²SEIDLER Ursula¹

1. Department of Gastroenterology,Hepatology and Endocrinology,Hannover Medical School,Hannover 30625,Germany 2. Department of Biochemistry,Erasmus University Medical Center,Rotterdam,Netherlands 3. Department of Medicine,Physiology and Cell Biology,Johns Hopkins University School of Medicine,Baltimore,MD 4. Department of Medicine,University of Maryland School of Medicine,Baltimore,MD 5. Department of Pathology,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA

摘要：＜正＞Heterologous expression studies have demonstrated that the PDZ-proteins NHERF1,NHERF2 and PDZK1 （NHERF3）modulate CFTR membrane expression,conductivity and interaction with other proteins.To study their biological roles in vivo in an epithelium that highly expresses both CFTR and all three NHERF proteins,we investigated the effect of NHERF1,2 and PDZK1 ablation,or a combination of the above,on duodenal HCO₃^- secretion in the basal state and after agonist and inhibitor application.The proximal duodenum of anesthetized mice was perfused in situ,and HCO₃^- secretion was determined by back-titration.NHERF1 ablation strongly reduced basal and forskolin（FSK）-stimulated HCO₃^- secretory rates,and completely preventedβ₂-adrenergic stimulation.NHERF2 deletion significantly augmented FSK-stimulated HCO₃^- secretion,prevented the inhibitory effect of LPA,and partially rescued the suppressed basal HCO₃ secretion resulting from NHERF1 ablation.PDZK1 ablation reduced basal HCO₃^- secretion but not the response to FSK.The deletion of CFTR abolished agonist-mediated HCO₃^- secretion and any effect of NHERF ablation.We conclude that the three NHERF proteins differentially modulate basal and agonist -mediated duodenal HCO₃ secretion in vivo in a CFTR-dependent fashion.NHERF1 is an obligatory linker forβ₂-Vadrenergic stimulation of CFTR,and strongly augments cAMP-mediated stimulation.NHERF2 confers inhibitory signals,i.e.as a coupling factor between inhibitory LPA receptors and CFTR.

关键词：

NHERF1; NHERF2; PDZK1; CFTR;

会议名称：

2008北京国际生理科学学术大会

会议时间：

2008-10

会议地点：

中国北京