Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases.
Mammalian airways are protected from infection by a thin film of airway surface liquid (ASL) which covers airway epithelial surfaces and acts as a lubricant to keep mucus from adhering to the epithelial surface. Precise regulation of ASL volume is essential for efficient mucus clearance and too great a reduction in ASL volume causes mucus dehydration and mucus stasis which contributes to chronic airway infection. The epithelial Na(+) channel (ENaC) is the rate-limiting step that governs Na(+) absorption in the airways. Recent in vitro and in vivo data have demonstrated that ENaC is a critical determinant of ASL volume and hence mucus clearance. ENaC must be cleaved by either intracellular furin-type proteases or extracellular serine proteases to be active and conduct Na(+), and this process can be inhibited by protease inhibitors. ENaC can be regulated by multiple pathways, and once proteolytically cleaved ENaC may then be inhibited by intracellular second messengers such as cAMP and PIP(2). In the airways, however, regulation of ENaC by proteases seems to be the predominant mode of regulation since knockdown of either endogenous serine proteases such as prostasin, or inhibitors of ENaC proteolysis such as SPLUNC1, has large effects on ENaC activity in airway epithelia. In this review, we shall discuss how ENaC is proteolytically cleaved, how this process can regulate ASL volume, and how its failure to operate correctly may contribute to chronic airway disease.
Gaillard
Erol A
EA
Department of Infection, Immunity and Inflammation, University of Leicester, PO Box 65, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
Kota
Pradeep
P
Gentzsch
Martina
M
Dokholyan
Nikolay V
NV
Stutts
M Jackson
MJ
Tarran
Robert
R
D000818:Animals; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D009079:Mucociliary Clearance; D011487:Protein Conformation; D020545:Respiratory Mucosa / Q000201:enzymology*; D012137:Respiratory System / Q000201:enzymology*; D012140:Respiratory Tract Diseases / Q000378:metabolism; D015290:Second Messenger Systems; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D053503:Epithelial Sodium Channels; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases
J Biol Chem. 1997 Oct 10;272(41):25537-41
9325269
Am J Respir Crit Care Med. 1994 Aug;150(2):448-54
8049828
J Biol Chem. 2005 Oct 21;280(42):35751-9
16087672
J Biol Chem. 2008 Dec 26;283(52):36586-91
18981180
Annu Rev Physiol. 2009;71:361-79
18928407
J Biol Chem. 2009 Oct 16;284(42):29024-40
19717556
Channels (Austin). 2010 Jul-Aug;4(4):255-9
20519934
Science. 1989 Sep 8;245(4922):1066-73
2475911
Am Rev Respir Dis. 1968 Sep;98(3):449-63
5691682
Respir Physiol Neurobiol. 2007 Dec 15;159(3):271-7
17707699
Am J Respir Cell Mol Biol. 2004 Feb;30(2):184-92
12920053
Am J Respir Cell Mol Biol. 2002 Mar;26(3):290-7
11867337
Lancet. 2008 Aug 2;372(9636):415-7
18675692
J Biol Chem. 2004 Mar 26;279(13):12529-34
14726523
Proc Am Thorac Soc. 2008 Sep 15;5(7):772-7
18757316
Respir Physiol Neurobiol. 2007 Dec 15;159(3):256-70
17692578
J Biol Chem. 2004 Apr 30;279(18):18111-4
15007080
Am J Respir Cell Mol Biol. 2008 Aug;39(2):190-7
18367727
N Engl J Med. 1990 Apr 26;322(17):1189-94
2157983
Contrib Microbiol. 2008;15:147-163
18511860
J Biol Chem. 2002 Apr 5;277(14):11965-9
11812779
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):444-50
17693760
Science. 1995 Aug 11;269(5225):847-50
7543698
N Engl J Med. 1999 Jul 15;341(3):156-62
10403853
J Biol Chem. 2007 Mar 2;282(9):6153-60
17199078
Curr Opin Pharmacol. 2009 Jun;9(3):262-7
19285919
J Biol Chem. 2007 Jan 5;282(1):58-64
17090546
Nature. 2007 Sep 20;449(7160):316-23
17882215
Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10282-7
10920189
Am J Physiol. 1998 Mar;274(3):L388-95
9530174
Biochim Biophys Acta. 2007 Apr;1773(4):476-9
17306384
J Biol Chem. 2002 Mar 8;277(10):7641-4
11809744
Am J Physiol Renal Physiol. 2009 Jan;296(1):F10-24
18508877
Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1099-109
15681398
J Virol. 2007 Apr;81(8):3714-20
17287265
J Exp Med. 2008 Jul 7;205(7):1529-34
18591408
FASEB J. 2005 Jan;19(1):142-3
15504951
J Leukoc Biol. 2004 Jan;75(1):34-8
12960278
Eur J Morphol. 1998 Aug;36 Suppl:67-73
9825896
Am J Physiol. 1997 Apr;272(4 Pt 1):C1077-86
9142832
IUBMB Life. 2008 Sep;60(9):620-8
18459164
Respir Physiol Neurobiol. 2008 Nov 30;163(1-3):208-13
18635403
J Gen Physiol. 2006 May;127(5):591-604
16636206
Hum Mol Genet. 2002 Apr 15;11(8):937-43
11971875
Am J Respir Crit Care Med. 1999 Jul;160(1):144-9
10390392
J Biol Chem. 2000 Sep 8;275(36):27947-56
10821834
Trends Biochem Sci. 2009 Sep;34(9):453-63
19726197
J Biol Chem. 2004 Jun 25;279(26):27729-34
15096495
Am J Physiol. 1999 Apr;276(4):C827-37
10199813
J Clin Invest. 2009 Sep;119(9):2613-22
19726884
Am J Physiol. 1997 Jul;273(1 Pt 1):L227-33
9252560
J Biol Chem. 2003 Apr 11;278(15):13468-79
12560324
Pflugers Arch. 1997 Dec;435(1):178-81
9359918
Am J Physiol. 1998 Jun;274(6):C1699-707
9611136
Structure. 2007 Dec;15(12):1567-76
18073107
EMBO Mol Med. 2010 Jan;2(1):26-37
20043279
J Biol Chem. 2001 Nov 9;276(45):42610-7
11560932
Science. 2008 Oct 24;322(5901):590-4
18772398
Nature. 1985 Oct 24-30;317(6039):730-2
3877243
Br J Pharmacol. 1991 Jul;103(3):1649-56
1718521
Am J Respir Med. 2003;2(4):299-309
14719996
Biophys J. 2001 May;80(5):2176-86
11325720
J Gen Physiol. 2007 Dec;130(6):611-29
17998393
J Clin Invest. 2007 Nov;117(11):3489-97
17948127
J Biol Chem. 1994 Jul 22;269(29):18843-8
8034638
J Biol Chem. 2005 Sep 9;280(36):31587-94
16027156
Am J Physiol Renal Physiol. 2008 Jan;294(1):F47-52
18032549
J Biol Chem. 2003 Sep 26;278(39):37073-82
12871941
J Biol Chem. 1998 May 29;273(22):13469-74
9593680
Am J Respir Crit Care Med. 1994 Jul;150(1):271-81
8025763
J Biol Chem. 2008 Mar 21;283(12):7455-63
18195015
J Clin Invest. 1986 Nov;78(5):1245-52
3771796
J Physiol. 2002 Sep 1;543(Pt 2):413-24
12205178
Proc Am Thorac Soc. 2004;1(1):47-53
16113412
Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11412-7
19541605
J Biol Chem. 2007 Nov 16;282(46):33475-33483
17855354
Annu Rev Physiol. 2006;68:543-61
16460283
Chest. 2005 Nov;128(5):3743-9
16304342
J Gen Physiol. 2007 Jul;130(1):55-70
17562820
Nature. 1999 Nov 18;402(6759):301-4
10580502
Mol Cell. 2001 Jul;8(1):149-58
11511368
Nature. 2008 Oct 30;455(7217):1210-5
18724360
Proc Am Thorac Soc. 2004;1(1):4-9
16113404
J Pharmacol Exp Ther. 2004 Dec;311(3):929-38
15273255
J Clin Invest. 1999 Oct;104(7):967-74
10510337
Am J Respir Crit Care Med. 2008 Dec 15;178(12):1245-56
18849497
Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2429-33
1549606
Br J Pharmacol. 2000 May;130(2):367-74
10807675
Curr Top Dev Biol. 2007;78:23-46
17338914
Am J Physiol Cell Physiol. 2002 Jul;283(1):C126-34
12055080
Am J Respir Cell Mol Biol. 1994 Sep;11(3):321-8
7522016
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5310-5
10220462
J Physiol. 2008 Oct 1;586(19):4587-608
18669538
J Physiol. 2009 May 15;587(Pt 10):2127-39
19015192
Endocrinology. 2005 Dec;146(12):5079-85
16150899
Am J Respir Cell Mol Biol. 2010 Apr;42(4):498-505
19520916
Am J Physiol. 1995 Jul;269(1 Pt 1):C188-97
7631745
Am J Physiol Lung Cell Mol Physiol. 2004 Nov;287(5):L928-35
15246975
Pflugers Arch. 2007 Oct;455(1):169-80
17605040
J Clin Invest. 1998 Jul 1;102(1):15-21
9649552
Am J Physiol Renal Physiol. 2005 Jan;288(1):F150-61
15454394
Am J Respir Crit Care Med. 2006 May 15;173(10):1139-44
16497995
J Biol Chem. 2004 Aug 27;279(35):36855-64
15210701
J Clin Invest. 1983 May;71(5):1410-7
6853720
J Am Soc Nephrol. 2006 Apr;17(4):968-76
16524950
Am J Respir Crit Care Med. 2006 Mar 1;173(5):475-82
16126935
Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66
12360192
Curr Opin Nephrol Hypertens. 2008 Sep;17(5):533-40
18695396
J Biol Chem. 2006 Mar 24;281(12):8233-41
16423824
Am J Physiol Lung Cell Mol Physiol. 2010 Apr;298(4):L473-82
20044437
Science. 1983 Sep 9;221(4615):1067-70
6308769
J Biol Chem. 2009 Mar 13;284(11):7294-306
19131335
J Clin Invest. 2002 Mar;109(5):571-7
11877463
Am J Physiol. 1992 Jul;263(1 Pt 1):L1-14
1322048
Cell. 2008 Sep 19;134(6):1019-29
18805094
Pflugers Arch. 2002 Jul;444(4):549-55
12136275
J Gen Physiol. 1997 Jan;109(1):15-26
8997662
Respir Res. 2003;4:8
14511398
J Gen Physiol. 2001 Aug;118(2):223-36
11479349
Am J Physiol Gastrointest Liver Physiol. 2002 May;282(5):G757-65
11960772
Am J Physiol Lung Cell Mol Physiol. 2001 Jul;281(1):L16-23
11404240
J Biol Chem. 2002 Mar 8;277(10):8338-45
11756432
PLoS Comput Biol. 2006 Jul 7;2(7):e85
16839198
Med Res Rev. 1999 Mar;19(2):179-97
10189177
J Biol Chem. 2001 Jun 15;276(24):21434-42
11274175
Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L813-9
15640288
J Anat. 2002 Oct;201(4):313-8
12430955
Am J Physiol Cell Physiol. 2004 Jan;286(1):C190-4
12967915
J Pharmacol Exp Ther. 2008 Apr;325(1):77-88
18218832
J Biol Chem. 2007 Dec 14;282(50):36534-42
17940289
Proc Am Thorac Soc. 2004;1(1):33-7
16113409
Clin Rev Allergy Immunol. 2008 Apr;34(2):146-62
17960347
J Biol Chem. 2004 May 7;279(19):20234-41
14993227
Am J Physiol Cell Physiol. 2007 Apr;292(4):C1553-61
17182731
Am Rev Respir Dis. 1990 Mar;141(3):605-12
2310093
Pharmacol Ther. 2006 Jun;110(3):415-32
16257449
Protein Sci. 2000 Sep;9(9):1753-73
11045621
Am J Physiol Lung Cell Mol Physiol. 2008 May;294(5):L932-41
18310226
N Engl J Med. 2006 Jan 19;354(3):241-50
16421365
Biophys J. 2009 Dec 16;97(12):3047-53
20006941
Eur Respir J. 1993 Oct;6(9):1243-8
8287938
J Am Soc Nephrol. 2000 May;11(5):828-834
10770960
Nat Med. 2004 May;10(5):487-93
15077107
Pflugers Arch. 2003 Jan;445(4):495-8
12548395
Am J Physiol Regul Integr Comp Physiol. 2009 Dec;297(6):R1733-41
19793956
J Gen Physiol. 2002 Aug;120(2):191-201
12149280
Nature. 1997 Oct 9;389(6651):607-10
9335501
EMBO J. 1997 Nov 3;16(21):6325-36
9351815
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):16083-8
14668433
J Pharmacol Exp Ther. 2009 May;329(2):764-74
19190233
Curr Drug Targets Inflamm Allergy. 2005 Dec;4(6):651-64
17305521
N Engl J Med. 2006 Jan 19;354(3):229-40
16421364
J Intern Med. 2007 Jan;261(1):5-16
17222164
Am J Physiol Cell Physiol. 2006 Aug;291(2):C218-30
16825601
J Membr Biol. 2004 Nov;202(1):21-37
15702377
Exp Lung Res. 2000 Apr-May;26(3):149-62
10813088
J Aerosol Med. 2000 Summer;13(2):73-86
11010597
J Biol Chem. 2006 Sep 22;281(38):27942-9
16873367
J Aerosol Med. 2003 Summer;16(2):121-9
12823906
J Biol Chem. 1997 May 30;272(22):14037-40
9162024
Physiol Rev. 2002 Jan;82(1):245-89
11773614
J Biol Chem. 2003 Mar 28;278(13):11256-64
12551890
Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L894-902
15626749
J Biol Chem. 1995 Nov 17;270(46):27411-4
7499195
J Biol Chem. 2001 Jan 12;276(2):1326-34
11022046
J Gen Physiol. 2008 Nov;132(5):521-35
18852303
Biochem J. 2007 Jul 1;405(1):147-55
17381423