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BMC Pharmacology and Toxicology

Open Access

cGMP-dependent kinase 2, Na+/H+ regulatory factor 2, and Na+/H+ exchanger isoform 3 assemble within lipid rafts in murine small intestinal brush border membrane

  • Min Luo1, 2,
  • Ayesha Sultan1,
  • Qin Yu1, 2,
  • Brigitte Riederer1,
  • Weiliang Xia1, 3,
  • Min Luo1, 2,
  • Mingmin Chen1,
  • Simone Lissner4,
  • Engelbert Gessner5,
  • Enrico Patrucco6,
  • Franz Hofmann6,
  • Mark Donowitz7,
  • Chris C Yun8,
  • Hugo de Jonge9,
  • Georg Lamprecht10 and
  • Ursula Seidler1Email author
BMC Pharmacology and Toxicology201314(Suppl 1):O31

Published: 29 August 2013

Trafficking, brush border membrane (BBM) retention, and signal-specific regulation of the Na+/H+ exchanger NHE3 is regulated by Na+/H+ Exchanger Regulatory Factor (NHERF) family of PDZ-adapter proteins, which enable the formation of multiprotein complexes. It is unclear, however, what determines signal specificity of the very homologous NHERFs. We studied the association of NHE3, as well as NHERF1 (EBP50), NHERF2 (E3KARP) and NHERF3 (PDZK1) with lipid rafts in murine small intestinal BBM and their possible association with signaling molecules. NHE3 was found to partially associate with glycosphingolipid-enriched microdomains in the native BBM, and NHE3 raft association had an impact on NHE3 transport activity as well as on second-messenger-dependent regulation in vivo. NHERF1, 2 and 3 were differentially distributed to rafts and non-rafts, with NHERF2 being most raft-associated and NHERF3 entirely non-raft associated. A search for other signalling molecules that are implicated in regulating NHE3 through a NHERF interaction, cGMP-dependent kinase II, which together with NHERF2 is essential for guanylin/heat stable enterotoxin of E.coli (STa)-mediated NHE3 inhibition in the intestine, was found exclusively lipid-raft associated. In conclusion, the differential association of the NHERFs, as well as kinases, with the raft-associated and the non-raft fraction of NHE3 in the brush border membrane is likely one component of the differential and signal-specific NHE3 regulation by the different NHERFs.

Authors’ Affiliations

Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School
Dept. of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology
Key Lab of Combined Multiorgan Transplantation, 1st Affiliated Hospital, School of Medicine, Zhejiang University
1st Medical Department, University of Tübingen
Dept. of Immunology and Rheumatology, Hannover Medical School
Forschergruppe 923, Institut für Pharmakologie und Toxikologie, TU München
Division of Gastroenterology, Department of Medicine and Physiology, John Hopkins School of Medicine
Division of Gastroenterology, Dept. of Medicine, Emory University
Dept. of Gastroenterology, Erasmus MC
Dept. of Gastroenterology, University of Rostock


© Luo et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.