The K+ channels K(Ca)3.1 and K(v)1.3 as novel targets for asthma therapy.
Asthma affects 10% of the UK population and is an important cause of morbidity and mortality at all ages. Current treatments are either ineffective or carry unacceptable side effects for a number of patients; in consequence, development of new approaches to therapy are important. Ion channels are emerging as attractive therapeutic targets in a variety of non-excitable cells. Ion channels conducting K(+) modulate the activity of several structural and inflammatory cells which play important roles in the pathophysiology of asthma. Two channels of particular interest are the voltage-gated K(+) channel K(v)1.3 and the intermediate conductance Ca(2+)-activated K(+) channel K(Ca)3.1 (also known as IK(Ca)1 or SK4). K(v)1.3 is expressed in IFNgamma-producing T cells while K(Ca)3.1 is expressed in T cells, mast cells, macrophages, airway smooth muscle cells, fibroblasts and epithelial cells. Both channels play important roles in cell activation, migration, and proliferation through the regulation of membrane potential and calcium signalling. We hypothesize that K(Ca)3.1- and/or K(v)1.3-dependent cell processes are one of the common denominators in asthma pathophysiology. If true, these channels might serve as novel targets for the treatment of asthma. Emerging evidence lends support to this hypothesis. Further validation through the study of the role that these channels play in normal and asthmatic airway cell (patho)physiology and in vivo models will provide further justification for the assessment of small molecule blockers of K(v)1.3 and K(Ca)3.1 in the treatment of asthma.
Bradding
Peter
P
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, UK. pbradding@hotmail.com
Wulff
Heike
H
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism*
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel
Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1084-9
18309114
Eur J Immunol. 2008 Sep;38(9):2548-56
18792407
Am Rev Respir Dis. 1980 Feb;121(2):389-413
6987924
Annu Rev Immunol. 2001;19:497-521
11244045
J Immunol. 1997 Jun 1;158(11):5120-8
9164927
J Allergy Clin Immunol. 2007 Oct;120(4):813-9
17610943
Mol Cell. 2006 Dec 8;24(5):665-675
17157250
J Clin Invest. 2008 Sep;118(9):3025-37
18688283
J Biol Chem. 2000 Jan 7;275(1):585-98
10617655
Allergy. 2004 May;59(5):469-78
15080825
Nature. 1998 Apr 30;392(6679):933-6
9582075
Curr Allergy Asthma Rep. 2003 Mar;3(2):166-71
12562557
Biochim Biophys Acta. 2003 Sep 22;1616(1):85-94
14507422
J Membr Biol. 1999 Dec 1;172(3):249-57
10568794
Nature. 2006 Sep 14;443(7108):226-9
16921385
J Exp Med. 1993 Mar 1;177(3):637-45
7679705
N Engl J Med. 2006 Feb 16;354(7):697-708
16481637
J Clin Invest. 2003 Jun;111(11):1703-13
12782673
Neuron. 1996 Feb;16(2):387-97
8789953
Nature. 1997 Apr 24;386(6627):855-8
9126747
J Gen Physiol. 1999 May;113(5):743-60
10228185
Mol Pharmacol. 2005 Nov;68(5):1254-70
16099841
Mol Pharmacol. 2005 Apr;67(4):1369-81
15665253
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14442-6
18796614
J Biol Chem. 1998 Dec 4;273(49):32697-707
9830012
Proc Natl Acad Sci U S A. 1990 Dec;87(23):9411-5
2251283
Thorax. 2004 Jul;59(7):557-62
15223860
Clin Exp Allergy. 2005 Feb;35(2):226-33
15725196
Am J Respir Crit Care Med. 2005 May 15;171(10):1103-8
15879427
J Allergy Clin Immunol. 2002 Dec;110(6):899-905
12464957
Eur J Immunol. 2005 Apr;35(4):1124-32
15756641
Am Rev Respir Dis. 1993 Sep;148(3):720-6
8368645
J Biol Chem. 1999 Feb 26;274(9):5746-54
10026195
Am J Respir Cell Mol Biol. 1996 Apr;14(4):319-26
8600935
Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):704-9
15662023
Am J Respir Crit Care Med. 2001 Aug 1;164(3):474-7
11500353
Am J Physiol. 1991 Jan;260(1 Pt 1):C104-12
1702932
Chest. 2006 Jul;130(1):244-50
16840409
Nature. 1992 Jan 23;355(6358):353-6
1309940
Mol Pharmacol. 2003 Feb;63(2):409-18
12527813
Nature. 2006 May 11;441(7090):179-85
16582901
Blood. 2003 Mar 15;101(6):2412-8
12433690
Science. 2006 May 26;312(5777):1220-3
16645049
FASEB J. 2005 Jun;19(8):1006-8
15817638
N Engl J Med. 2004 Aug 5;351(6):560-74
15295049
J Allergy Clin Immunol. 2001 Apr;107(4):664-70
11295656
Am J Respir Cell Mol Biol. 2007 Nov;37(5):525-31
17585114
J Allergy Clin Immunol. 2004 Jul;114(1):66-72
15241346
Blood. 2008 Apr 15;111(8):3991-7
18192510
Curr Med Chem. 2007;14(13):1437-57
17584055
J Immunol. 1997 Dec 15;159(12):6209-15
9550424
Immunity. 2008 Oct 17;29(4):602-14
18835197
Pflugers Arch. 2009 Jun;458(2):291-302
19037656
Am J Respir Crit Care Med. 2009 Apr 1;179(7):549-58
19136369
Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2493-503
16798818
J Physiol. 1985 Jan;358:197-237
2580081
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8151-6
10884437
Pharmacotherapy. 2006 Nov;26(11):1557-64
17064199
Circulation. 2003 Sep 2;108(9):1119-25
12939222
Am J Respir Cell Mol Biol. 1994 May;10(5):471-80
8179909
J Biol Chem. 2004 Nov 12;279(46):47681-7
15347667
Nat Rev Mol Cell Biol. 2000 Oct;1(1):11-21
11413485
Am Rev Respir Dis. 1990 May;141(5 Pt 1):1327-32
2187387
Am J Respir Crit Care Med. 2005 Jul 15;172(2):149-60
15849323
J Allergy Clin Immunol. 2006 Jun;117(6):1277-84
16750987
Clin Exp Allergy. 2008 Jun;38(6):872-97
18498538
Biochim Biophys Acta. 1999 Aug 20;1420(1-2):231-40
10446306
J Allergy Clin Immunol. 2004 Apr;113(4):690-6
15100675
Mol Pharmacol. 2009 Feb;75(2):281-95
18955585
J Biol Chem. 2003 Mar 14;278(11):9928-37
12511563
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13942-7
11717451
Nature. 2005 Oct 6;437(7060):902-5
16208375
J Biol Chem. 2001 Apr 13;276(15):12249-56
11278890
Eur J Immunol. 2007 Jun;37(6):1653-62
17474152
Curr Biol. 2007 May 1;17(9):794-800
17442569
Lancet. 2006 Aug 26;368(9537):733-43
16935684
J Invest Dermatol. 2007 Jun;127(6):1419-29
17273162
Thorax. 2006 Oct;61(10):880-5
16809411
J Cell Physiol. 2006 Jan;206(1):86-94
15965951
Trends Pharmacol Sci. 2004 May;25(5):280-9
15120495
Am J Respir Crit Care Med. 2003 Jan 1;167(1):71-7
12502478
J Immunol. 2000 Feb 1;164(3):1153-60
10640725
Chem Immunol Allergy. 2005;87:163-178
16107771
Br J Pharmacol. 2008 Mar;153 Suppl 2:S1-209
18347570
Circ Res. 2006 Sep 1;99(5):537-44
16873714
Eur J Biochem. 1996 Dec 15;242(3):491-8
9022673
Am J Physiol Cell Physiol. 2007 Apr;292(4):C1431-9
17151145
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17414-9
17088564
FASEB J. 2000 Jul;14(10):1362-74
10877829
Thorax. 2002 Aug;57(8):677-82
12149526
J Biol Chem. 2000 Nov 24;275(47):37137-49
10961988
N Engl J Med. 1992 Jan 30;326(5):298-304
1530827
J Immunol. 2001 Oct 15;167(8):4261-70
11591748
Ann Intern Med. 2003 Sep 2;139(5 Pt 1):359-70
12965945
Lancet. 2002 Nov 30;360(9347):1715-21
12480423
Am J Respir Cell Mol Biol. 1990 Nov;3(5):507-11
2223105
Nature. 2006 Sep 14;443(7108):230-3
16921383
Exp Biol Med (Maywood). 2007 Nov;232(10):1338-54
17959847
Clin Exp Allergy. 1999 Jun;29 Suppl 2:90-5
10421830
J Immunol. 2008 Jun 15;180(12):8040-7
18523267