Membrane surface charge dictates the structure and function of the epithelial Na+/H+ exchanger.
The Na(+)/H(+) exchanger NHE3 plays a central role in intravascular volume and acid-base homeostasis. Ion exchange activity is conferred by its transmembrane domain, while regulation of the rate of transport by a variety of stimuli is dependent on its cytosolic C-terminal region. Liposome- and cell-based assays employing synthetic or recombinant segments of the cytosolic tail demonstrated preferential association with anionic membranes, which was abrogated by perturbations that interfere with electrostatic interactions. Resonance energy transfer measurements indicated that segments of the C-terminal domain approach the bilayer. In intact cells, neutralization of basic residues in the cytosolic tail by mutagenesis or disruption of electrostatic interactions inhibited Na(+)/H(+) exchange activity. An electrostatic switch model is proposed to account for multiple aspects of the regulation of NHE3 activity.
Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
Robert Todd
RT
Alexander
Valentin
V
Jaumouillé
Tony
T
Yeung
Wendy
W
Furuya
Iskra
I
Peltekova
Annie
A
Boucher
Michael
M
Zasloff
John
J
Orlowski
Sergio
S
Grinstein
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004285:Dogs; D055724:Electrophysiological Phenomena; D008954:Models, Biological; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013499:Surface Properties
D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers
Biochemistry. 2000 Feb 29;39(8):1990-2000
10684649
Biochim Biophys Acta. 1994 Nov 2;1195(2):281-6
7947922
J Biol Chem. 2004 May 21;279(21):21833-40
15007075
J Biol Chem. 1998 Jan 23;273(4):2035-43
9442041
J Biol Chem. 2003 May 9;278(19):16494-501
12595524
Proteins. 2006 Aug 15;64(3):575-86
16763996
Biochemistry. 1979 May 29;18(11):2210-8
36128
Proc Natl Acad Sci U S A. 1984 Jun;81(12):3751-5
6587389
Am J Physiol. 1999 Jan;276(1):C136-44
9886929
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12253-8
16103375
J Gen Physiol. 2005 Jul;126(1):41-53
15955874
Prog Lipid Res. 2005 Jul;44(4):207-34
15979148
Biochemistry. 2000 Jul 11;39(27):8102-12
10891093
Am J Physiol Cell Physiol. 2000 Nov;279(5):C1443-54
11029292
J Biol Chem. 1997 Nov 7;272(45):28672-9
9353335
J Biol Chem. 1993 Dec 5;268(34):25527-35
8244988
Physiol Rev. 2007 Jul;87(3):825-72
17615390
Acta Physiol (Oxf). 2006 May-Jun;187(1-2):159-67
16734752
Nat Genet. 1998 Jul;19(3):282-5
9662405
Science. 2006 Jul 21;313(5785):347-51
16857939
J Gen Physiol. 2007 Sep;130(3):329-34
17698595
Cell Physiol Biochem. 2008;22(5-6):693-704
19088451
Am J Physiol. 1998 Oct;275(4):F478-86
9755119
J Biol Chem. 1995 Jun 9;270(23):13716-25
7775426
Nat Rev Mol Cell Biol. 2005 Mar;6(3):209-20
15738987
J Clin Invest. 1999 Dec;104(11):1593-602
10587523
J Cell Sci. 2004 Jul 1;117(Pt 15):3353-65
15226406
J Biol Chem. 2007 Mar 9;282(10):7376-84
17218318
J Biol Chem. 2002 Jun 28;277(26):23714-24
11948184
J Biol Chem. 2002 Mar 29;277(13):11090-6
11792708
Science. 2008 Jan 11;319(5860):210-3
18187657
Science. 2003 Jun 20;300(5627):1922-6
12738871
J Cell Biol. 2000 Jul 10;150(1):213-24
10893269
Cell. 1999 Jul 9;98(1):69-80
10412982
J Biol Chem. 1996 Feb 16;271(7):3590-9
8631966
Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1354-8
8433993
J Biol Chem. 2010 Aug 20;285(34):26652-61
20551318
J Biol Chem. 1999 Feb 12;274(7):3978-87
9933588
J Cell Sci. 1996 May;109 ( Pt 5):929-39
8743940
Nature. 2005 Dec 1;438(7068):605-11
16319880
J Biol Chem. 2002 Sep 13;277(37):34401-12
12097325
Am J Physiol Renal Physiol. 2007 Jul;293(1):F212-8
17409282
Am J Physiol Cell Physiol. 2003 Dec;285(6):C1527-36
12954600
Curr Opin Cell Biol. 2006 Aug;18(4):429-37
16781133
J Nat Prod. 2000 May;63(5):631-5
10843574
Nature. 2002 Jan 24;415(6870):389-95
11807545
Mol Membr Biol. 2009 Jan;26(1):80-92
19115142
Mol Biol Cell. 2006 Jun;17(6):2661-73
16540524
J Biol Chem. 1994 Sep 23;269(38):23544-52
8089122
Am J Physiol. 1999 Jun;276(6):C1303-11
10362593
Trends Biochem Sci. 1995 Jul;20(7):272-6
7667880
Biochemistry. 2000 Jul 18;39(28):8298-307
10889039
J Biol Chem. 1994 Jun 3;269(22):15613-8
8195209
Am J Physiol Renal Physiol. 2003 Jun;284(6):F1190-8
12582007