Activity and PI3-kinase dependent trafficking of the intestinal anion
exchanger downregulated in adenoma depend on its PDZ interaction
and on lipid rafts
S. Lissner,1L. Nold,1C.-J. Hsieh,1J. R. Turner,2M. Gregor,1L. Graeve,3and G. Lamprecht1
11st Medical Department, University of Tübingen, Tübingen, Germany,2Department of Pathology, University of Chicago,
Chicago, Illinois; and3Department of Biological Chemistry and Nutrition, University of Hohenheim, Hohenheim, Germany
Submitted 22 April 2010; accepted in final form 14 July 2010
Lissner S, Nold L, Hsieh C-J, Turner JR, Gregor M, Graeve L,
Lamprecht G. Activity and PI3-kinase dependent trafficking of the
intestinal anion exchanger downregulated in adenoma depend on its
PDZ interaction and on lipid rafts. Am J Physiol Gastrointest Liver
Physiol 299: G907–G920, 2010. First published July 15, 2010;
doi:10.1152/ajpgi.00191.2010.—The Cl/HCO3exchanger downregu-
lated in adenoma (DRA) mediates electroneutral NaCl absorption in
the intestine together with the apical Na/H exchanger NHE3. Lipid
rafts (LR) modulate transport activity and are involved in phosphati-
dylinositol 3-kinase (PI3-kinase)-dependent trafficking of NHE3. Al-
though DRA and NHE3 interact via PDZ adaptor proteins of the
NHERF family, the role of LR and PDZ proteins in the regulation of
DRA is unknown. We examined the association of DRA with LR
using the nonionic detergent Triton X-100. DRA cofractionated with
LR independently of its PDZ binding motif. Furthermore, DRA
interacts with PDZK1, E3KARP, and IKEPP in LR, although their
localization within lipid rafts is independent of DRA. Disruption of
LR integrity resulted in the disappearance of DRA from LR, in a
decrease of its surface expression and in a reduction of its activity. In
HEK cells the inhibition of DRA by LR disruption was entirely
dependent on the presence of the PDZ interaction motif. In addition,
in Caco-2/BBE cells the inhibition by LR disruption was more
pronounced in wild-type DRA than in mutated DRA (DRA-ETKFmi-
nus; lacking the PDZ binding motif)-expressing cells. Inhibition of
PI3-kinase decreased the activity and the cell surface expression of
wild-type DRA but not of DRA-ETKFminus; the partitioning into LR
was unaffected. Furthermore, simultaneous inhibition of PI3-kinase
and disruption of LR did not further decrease DRA activity and cell
surface expression compared with LR disruption only. These results
suggest that the activity of DRA depends on its LR association, on its
PDZ interaction, and on PI3-kinase activity.
Cl/HCO3exchange; PDZK1; E3KARP; NHERF; IKEPP
ELECTRONEUTRAL NaCl absorption in the ileum and proximal
colon is a major regulator of total body volume and electrolyte
homeostasis. Such absorption is mediated by the integrated
actions of the Na/H exchanger NHE3 (SLC9A3) and the
Cl/HCO3 exchanger downregulated in adenoma (DRA;
SLC26A3). Proof for the importance of these two transporters
comes from the respective knockout mice (40, 41), which
suffer from chronic diarrhea, as well as the rare human disease
congenital chloride diarrhea, which is caused by a loss-of-
function mutation of DRA (14). Much more common though is
impairment of this fundamental process by various infectious or
toxic agents leading to acute secretory diarrhea (9). To address
these diseases it is necessary to understand the physiological
regulation of transport proteins within enterocytes as well as the
responsible extra- and intracellular signal transduction pathways.
With regard to the regulation and the intracellular trafficking of
DRA NHE3 may serve as a paradigm, since the functions of
NHE3 and DRA appear to be regulated in parallel (21, 23).
Lipid rafts are sphingolipid- and cholesterol-rich membrane
microdomains, which have been operationally defined based
on their detergent insolubility and requirement of cholesterol
for their physiochemical and functional integrity (4, 36). Lipid
rafts were initially linked to caveolae and endocytosis but a
more detailed picture has emerged, where complexes consist-
ing of various sets of signal, adaptor and membrane proteins
are temporarily gathered in lipid rafts. Based on functional data
these complexes are involved in cellular processes that include
membrane sorting and recycling, protein trafficking (10, 12,
15), and cell signaling (35, 43).
A subset of transport proteins are localized within lipid rafts
and these have been implicated in their activity, trafficking and
membrane retention as well as their regulation. For instance,
disruption of raft integrity leads to decreased transport activity
of NHE3 (32), the kidney-specific sodium potassium chloride
cotransporter (NKCC2) (47), the serotonin transporter (30),
and the calcium ATPase (PMCA) (18). At least for NHE3 the
situation is complex in that its lipid raft localization is neces-
sary not only for its normal activity but also for its basal and
stimulated trafficking (27). Lipid rafts are involved in phos-
phatidylinositol-3 (PI3)-kinase-dependent exocytosis of NHE3
as well as in its basal endocytosis (32).
Both DRA and NHE3 possess PDZ binding motifs, which
allow an interaction with members of the NHERF family of
PDZ adaptor proteins (23). PDZ domain adaptor proteins have
been named after the first three proteins in which they were
discovered: PSD95, ZO1, and disc large. The four members of
the NHERF family of PDZ proteins, NHERF, E3KARP,
PDZK1 and IKEPP, as well as Shank2 and CAL, appear to
play important roles for the regulation of intestinal ion trans-
port (23). Several PDZ adaptor proteins also associate with
membrane rafts. The postsynaptic density protein-95 (PSD95)
directly associates with membrane rafts via covalently attached
palmitoyl groups (7). Thereby it modulates the cell surface
expression in lipid rafts of the voltage-gated potassium channel
(Kv 1.4) (49), of the acid-sensing ion channel 3 (ASIC3) (8),
and of the neuregulin receptor, ErbB4 (29). In T lymphocytes,
NHERF links lipid rafts to the cytoskeleton by binding to both
the lipid raft protein Cbp (COOH-terminal SRC kinase-asso-
ciated membrane adaptor protein) and the actin-binding protein
ezrin. This complex formation allows targeting of protein
kinase A type I to lipid rafts (17, 38).
Address for reprint requests and other correspondence: G. Lamprecht, 1st
Medical Dept., Univ. of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen,
Germany (e-mail: email@example.com).
Am J Physiol Gastrointest Liver Physiol 299: G907–G920, 2010.
First published July 15, 2010; doi:10.1152/ajpgi.00191.2010.
0193-1857/10 Copyright © 2010 the American Physiological Societyhttp://www.ajpgi.org G907
Although the role of the NHERF family of adaptor proteins
for the regulation, targeting, and trafficking of NHE3 and
CFTR has been studied extensively, there is currently no
general picture emerging (23). With regard to NHE3, DRA,
and their common function for intestinal NaCl absorption the
potential interplay of their raft association and their PDZ
interaction has not been studied. To this end DRA has the
advantage that a mutant, which lacks the PDZ interaction motif
(DRA-ETKFminus), can be expressed and is functionally ac-
Thus we tested the hypothesis that DRA is localized in lipid
rafts and addressed the functional role of the PDZ interaction
of DRA. Moreover, we analyzed whether lipid rafts are in-
volved in PI3-kinase-dependent insertion of DRA into the
Materials. Nigericin, methyl-?-cyclodextrin (MCD), and Triton
X-100 were from Sigma-Aldrich (Steinheim, Germany). BCECF-AM,
LY294002, and the lipid raft labeling kit (Vybrant Alexa Fluor 594)
were from Invitrogen (Paisley, Scotland). Sulfo-NHS-SS-biotin,
NeutrAvidin agarose, and protein A-Sepharose were from Pierce
(Rockford, IL). Complete protease inhibitor mixture was from Roche
Applied Science (Mannheim, Germany). The monoclonal antibody
against enhanced green fluorescent protein (EGFP) was from Clon-
tech (Mountain View, CA). The monoclonal antibodies against flo-
tillin, Rab5 and Akt were from BD Transduction (Franklin Lakes, NJ).
The polyclonal antibodies against phosphorylated Akt (threonine-
308-P and serine-473-P) were from Cell Signaling Technology (Dan-
vers, MA). Anti-mouse secondary antibody and Anti-rabbit secondary
antibody were from Dianova (Hamburg, Germany). FluorSave Re-
agent was from Merck (Darmstadt, Germany).
Cell lines. HEK293 cells stably transfected with EGFP-tagged
DRA (HEK/EGFP-DRA) or EGFP-tagged DRA-ETKFminus (HEK/
EGFP-DRA-ETKFminus); a DRA construct that lacks the COOH-
terminal PDZ interaction motif (glutamate-threonine-lysine-phenylal-
anine, ETKF), were used as described previously (20). Caco-2/BBE
cells expressing the Tet-Off system stably transfected with EGFP-
DRA and EGFP-DRA-ETKFminus were used as described previously
(24). They were routinely kept in the presence of 20 ng/ml doxycy-
cline. Only for functional studies the expression of the DRA con-
structs was induced by growth in the absence of doxycycline and the
cells were used 10 days after reaching confluence.
Expression constructs. EGFP-PDZK1 was used as described pre-
viously (24). Human NHERF (also known as EBP50) was amplified
from the Imagenes clone IRAKp961A113 using pfu and primers that
incorporate a BamHI and a XhoI site (CCTTAGGGATCCAT-
GAGCGCGGACG and GGCTCGAGGGCGCTCAGAGGTTGC).
The PCR product was cloned into pCR-II-blunt TOPO (Invitrogen),
sequenced and shuttled into pEGFP-C1 (Clontech) by using BamHI
and XbaI (in this case originating from the pCR-II-blunt vector back
bone), resulting in pEGFP-C1/NHERF. E3KARP was reamplified by
using pfu from pBS/E3KARP (50) using primers that introduce a
BamHI and a SalI site (CGGCTTTTAGGATCCATGGCCGC and
GCAGGAGTCGACTCAGAAGTTGCTGAA). The PCR product
was cloned into pCR-II-blunt TOPO (Invitrogen), sequenced and
shuttled into pEGFP-C1 (Clontech) using BamHI and XbaI (in this
case originating from the pCR-II-blunt vector back bone) resulting in
pEGFP-C1/E3KARP. The coding sequence of IKEPP was amplified
from the Imagenes clone IRAKp961G0550Q using pfu and primers
that incorporate a HindIII and a XbaI site (GAAGCTTCTATG-
GAGAAAGCCGCAGATC and TCTGTATCTAGAAGGGGTGC-
TCTACAGTAG). The PCR product was cloned into pCR-II-blunt
TOPO, sequenced and shuttled into pEGFP-C1 (Clontech) using
HindIII and XbaI resulting in pEGFP-C1/IKEPP.
Cell transfection. Subconfluent (?70% confluence) HEK/EGFP-
DRA or HEK/EGFP-DRA-ETKFminus cells were transiently trans-
fected in tissue culture flasks (25 cm2) using 10 ?g expression
construct of the PDZ adaptor proteins and 20 ?l Lipofectamine 2000
according to the recommendations of the manufacturer (Invitrogen).
The cells were used 24 h after transfection.
Sucrose flotation gradient. Confluent monolayers in tissue culture
flask (50 cm2) were washed twice with ice-cold PBS and lysed in 2 ml
TNE buffer (25 mM Tris·HCl pH 7.5, 150 mM NaCl, 5 mM EDTA)
containing protease inhibitor cocktail and 1% Triton X-100 (3, 37).
The cells were scraped and homogenized with 10 strokes in a Dounce
homogenizer. 2 ml of this lysate was mixed with an equal volume of
80% (wt/vol) sucrose in TNE buffer with protease inhibitor, trans-
ferred into a ultracentrifuge tube, and overlaid with 4 ml of 30%
(wt/vol) sucrose and finally with 5% (wt/vol) sucrose (both in TNE
buffer with protease inhibitor). Centrifugation was done in a Beckman
SW41Ti rotor at 170,000 g for 19 h at 4°C. Twelve fractions were
collected from the top of the gradient. In these fractions proteins were
precipitated with trichloroacetic acid (TCA), size separated by 8.5%
SDS-PAGE, and transferred onto nitrocellulose membranes.
MCD treatment. For cholesterol depletion 10 days confluent mono-
layers of Caco-2/BBE cells or 2 days confluent monolayers of HEK
cells were treated with 20 mM or 1 mM MCD, respectively, in
DMEM plus 0.2% BSA at 37°C for 60 min as indicated. The cells
Fig. 1. Association of downregulated in adenoma (DRA) and DRA-ETKFmi-
nus with lipid rafts in stably transfected HEK cells. HEK/EGFP-DRA (A) and
HEK/EGFP-DRA-ETKFminus cells (B) were lysed at 4°C using 1% Triton
X-100. The lysates were subjected to sucrose density centrifugation. As a raft
marker flotillin was detected in the low-density fractions 3-6 and as a nonraft
marker rab5 was detected in the high-density fractions. Both EGFP-DRA and
EGFP-DRA-ETKFminus were consistently detected in both low-density (lipid
raft) as well as high-density (nonraft) fractions, suggesting that DRA is
partially localized within lipid rafts independently of its interaction with PDZ
adaptor proteins. Representative data of 5 experiments. EGFP, enhanced green
DRA IS LOCALIZED WITHIN LIPID RAFTS
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Fig. 13. DRA interacts with the PDZ adaptor proteins PDZK1, E3KARP, and
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