The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II

Peijian He; Luqing Zhao; Yi Ran No; Serhan Karvar; C Chris Yun

doi:10.1152/ajprenal.00247.2016

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The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II

Journal article

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The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II

Peijian He, Luqing Zhao, Yi Ran No, Serhan Karvar and C Chris Yun

American journal of physiology. Renal physiology, Vol.311(2), pp.F343-F351

08/01/2016

DOI: 10.1152/ajprenal.00247.2016

PMCID: PMC6189742

PMID: 27279487

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Abstract

Na(+)/H(+) exchanger (NHE)3, a major Na(+) transporter in the luminal membrane of the proximal tubule, is subject to ANG II regulation in renal Na(+)/fluid absorption and blood pressure control. We have previously shown that inositol 1,4,5-trisphosphate receptor-binding protein released with inositol 1,4,5-trisphosphate (IRBIT) mediates ANG II-induced exocytosis of NHE3 in cultured proximal tubule epithelial cells. In searching for scaffold protein(s) that coordinates with IRBIT in NHE3 trafficking, we found that NHE regulatory factor (NHERF)1, NHE3, and IRBIT proteins were coexpressed in the same macrocomplexes and that loss of ANG II type 1 receptors decreased their expression in the renal brush-border membrane. We found that NHERF1 was required for ANG II-mediated forward trafficking and activation of NHE3 in cultured cells. ANG II induced a concomitant increase of NHERF1 interactions with NHE3 and IRBIT, which were abolished when the NHERF1 PDZ1 domain was removed. Overexpression of a yellow fluorescent protein-NHERF1 construct that lacks PDZ1, but not PDZ2, failed to exaggerate the ANG II-dependent increase of NHE3 expression in the apical membrane. Moreover, exogenous expression of PDZ1 exerted a dominant negative effect on NHE3 activation by ANG II. We further demonstrated that IRBIT was indispensable for the ANG II-provoked increase in NHERF1-NHE3 interactions and that phosphorylation of IRBIT at Ser(68) was necessary for the assembly of the NHEF1-IRBIT-NHE3 complex. Taken together, our findings suggest that NHERF1 mediates ANG II-induced activation of renal NHE3, which requires coordination between IRBIT and the NHERF1 PDZ1 domain in binding and transporting NHE3.

Adenosylhomocysteinase - metabolism

Angiotensin II - pharmacology

Animals

Biotinylation

Cell Line

Hydrogen-Ion Concentration

Mice

Mice, Knockout

Microvilli - metabolism

Phosphoproteins - metabolism

Plasmids - genetics

Receptor, Angiotensin, Type 1 - drug effects

Receptor, Angiotensin, Type 1 - genetics

Receptor, Angiotensin, Type 1 - metabolism

Sodium - metabolism

Sodium-Hydrogen Exchanger 3

Sodium-Hydrogen Exchangers - agonists

Sodium-Hydrogen Exchangers - metabolism

Details

Title: Subtitle: The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II
Creators: Peijian He - Emory University
Luqing Zhao - Emory University
Yi Ran No - Emory University
Serhan Karvar - Medical University of South Carolina
C Chris Yun - Emory University
Resource Type: Journal article
Publication Details: American journal of physiology. Renal physiology, Vol.311(2), pp.F343-F351
DOI: 10.1152/ajprenal.00247.2016
PMID: 27279487
PMCID: PMC6189742
ISSN: 1931-857X
eISSN: 1522-1466
Grant note: I01 BX002540 / BLRD VA R01 DK061418 / NIDDK NIH HHS R01 DK107719 / NIDDK NIH HHS
Language: English
Date published: 08/01/2016
Academic Unit: Internal Medicine
Record Identifier: 9984695836202771

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