KV7 channelopathies.
KV7 voltage-gated potassium channels, encoded by the KCNQ gene family, have caught increasing interest of the scientific community for their important physiological roles, which are emphasized by the fact that four of the five so far identified members are related to different hereditary diseases. Furthermore, these channels prove to be attractive pharmacological targets for treating diseases characterized by membrane hyperexcitability. KV7 channels are expressed in brain, heart, thyroid gland, pancreas, inner ear, muscle, stomach, and intestines. They give rise to functionally important potassium currents, reduction of which results in pathologies such as long QT syndrome, diabetes, neonatal epilepsy, neuromyotonia, or progressive deafness. Here, we summarize some key traits of KV7 channels and review how their molecular deficiencies could explain diverse disease phenotypes. We also assess the therapeutic potential of KV7 channels; in particular, how the activation of KV7 channels by the compounds retigabine and R-L3 may be useful for treatment of epilepsy or cardiac arrhythmia.
Maljevic
Snezana
S
Department of Neurology and Epileptology, Center for Neurology, Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
Wuttke
Thomas V
TV
Seebohm
Guiscard
G
Lerche
Holger
H
D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D053447:Channelopathies / Q000235:genetics / Q000503:physiopathology*; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D008133:Long QT Syndrome / Q000235:genetics; D009154:Mutation; D010655:Phenylenediamines / Q000494:pharmacology
D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; C101866:ezogabine
Nat Rev Neurosci. 2000 Oct;1(1):21-30
11252765
J Neurosci. 2001 Feb 15;21(4):1096-103
11160379
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4914-9
10781098
Adv Otorhinolaryngol. 2002;61:41-6
12408061
Epilepsy Res. 2005 Jul;65(3):161-8
16039833
Cardiovasc Res. 2005 Aug 15;67(3):529-38
16039274
Brain. 2002 Aug;125(Pt 8):1887-95
12135978
Nat Med. 2009 Oct;15(10):1186-94
19767733
Hum Genet. 2008 Feb;123(1):41-53
18030493
Ann Neurol. 1999 Sep;46(3):305-12
10482260
J Hum Genet. 2001;46(7):355-61
11450843
Neurology. 2007 Nov 27;69(22):2045-53
17872363
J Biol Chem. 2006 Jan 6;281(1):418-28
16260777
J Neurosci. 2005 May 18;25(20):5051-60
15901787
Nat Genet. 1994 Oct;8(2):136-40
7842011
J Biol Chem. 2000 Jul 21;275(29):22395-400
10787416
Audiol Neurootol. 2007;12(1):20-6
17033161
Ann Noninvasive Electrocardiol. 2009 Jan;14(1):72-9
19149796
Nat Genet. 1998 Jan;18(1):53-5
9425900
Neurology. 2003 Jul 8;61(1):131-4
12847176
EMBO J. 2000 Feb 1;19(3):332-40
10654932
Nat Genet. 2008 Sep;40(9):1098-102
18711366
J Am Soc Nephrol. 2001 Oct;12(10):2003-2011
11562398
Epilepsia. 2009 Jul;50(7):1752-9
19453707
Nature. 1980 Feb 14;283(5748):673-6
6965523
J Med Genet. 2007 Dec;44(12):791-6
17675531
Biochem Soc Trans. 2007 Nov;35(Pt 5):1074-6
17956282
Nature. 2002 Apr 25;416(6883):874-8
11976689
Genet Med. 2008 Nov;10(11):797-804
18941426
Mol Pharmacol. 1998 Jul;54(1):220-30
9658209
EMBO Rep. 2003 Jan;4(1):76-81
12524525
Mol Pharmacol. 2009 Feb;75(2):272-80
19015229
J Neurosci. 2004 Feb 4;24(5):1236-44
14762142
J Physiol. 2008 Jul 15;586(14):3405-23
18483067
J Physiol. 2008 Nov 15;586(22):5437-53
18801845
Neurology. 2004 Jul 13;63(1):57-65
15249611
FEBS Lett. 1998 Nov 6;438(3):171-6
9827540
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12272-7
11572947
Circ Res. 2003 Nov 14;93(10):941-7
14576198
Hum Mutat. 1999;14(6):493-501
10571947
Hum Mutat. 2002 Jul;20(1):15-9
12112653
Mutat Res. 2009 Mar-Jun;681(2-3):189-196
18804553
Mol Pharmacol. 2005 Apr;67(4):1053-66
15598972
J Biol Chem. 2002 Jul 12;277(28):25187-94
11994278
Circ Res. 2007 Mar 16;100(5):686-92
17293474
Nature. 1996 Nov 7;384(6604):80-3
8900283
Trends Pharmacol Sci. 2008 Feb;29(2):99-107
18206251
Pflugers Arch. 2005 Dec;451(3):428-36
16133261
Hum Mol Genet. 1999 Jul;8(7):1321-8
10369879
Ann Neurol. 2000 Jun;47(6):822-6
10852552
Neurosci Lett. 2000 Mar 17;282(1-2):73-6
10713399
Ann Noninvasive Electrocardiol. 2003 Jul;8(3):246-50
14510661
J Biol Chem. 2000 May 5;275(18):13343-8
10788442
J Physiol. 2003 Apr 15;548(Pt 2):353-60
12640002
J Biol Chem. 2001 Apr 27;276(17):13600-5
11278406
Mol Pharmacol. 2007 Jun;71(6):1503-11
17347319
Epilepsy Res. 2003 Apr;54(1):21-7
12742592
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4333-8
10760300
Physiology (Bethesda). 2005 Dec;20:408-16
16287990
Otol Neurotol. 2005 Jan;26(1):52-8
15699719
Brain. 2003 Dec;126(Pt 12):2726-37
14534157
J Biol Chem. 1998 Dec 18;273(51):34069-74
9852064
Neuroreport. 2000 Jun 26;11(9):2063-7
10884071
Biochemistry. 2008 Aug 5;47(31):7999-8006
18611041
Mol Pharmacol. 2005 Apr;67(4):1009-17
15662042
Biochem Biophys Res Commun. 2007 Jun 22;358(1):304-10
17482572
J Mol Cell Cardiol. 2005 Feb;38(2):277-87
15698834
Sci Transl Med. 2009 Oct 14;1(2):2ra6
20368164
Ann Med. 2006;38(4):294-304
16754261
Am J Physiol Regul Integr Comp Physiol. 2002 Mar;282(3):R639-48
11832382
Circulation. 1991 Apr;83(4 Suppl):II71-80
2009631
Science. 1998 Dec 4;282(5395):1890-3
9836639
Expert Opin Investig Drugs. 2006 Oct;15(10):1167-77
16989594
J Neurosci. 2004 Oct 13;24(41):9146-52
15483133
Pediatr Neurol. 1997 Apr;16(3):249-51
9165519
J Physiol. 2005 Mar 1;563(Pt 2):359-68
15649981
Science. 1998 Jan 16;279(5349):403-6
9430594
J Neurosci. 2007 May 2;27(18):4919-28
17475800
Am J Physiol Cell Physiol. 2004 Jun;286(6):C1453-63
14761891
Epilepsy Res. 2008 Mar;79(1):1-5
18249525
J Hum Genet. 2006;51(5):455-460
16596322
Heart Rhythm. 2009 Aug;6(8):1154-5
19560405
Hum Mol Genet. 1997 Oct;6(11):1943-9
9302275
Am J Med Genet. 2000 Jul 31;93(3):184-7
10925378
Curr Med Chem Cardiovasc Hematol Agents. 2003 Oct;1(3):243-52
15326915
Nat Genet. 1996 Jan;12(1):17-23
8528244
J Biol Chem. 2000 Aug 4;275(31):24089-95
10816588
J Biol Chem. 2009 Jul 31;284(31):20668-75
19494108
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1478-82
18223154
Cell. 1999 Feb 5;96(3):437-46
10025409
Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H664-70
12124214
Mol Pharmacol. 2002 Apr;61(4):921-7
11901232
Channels (Austin). 2010 Mar-Apr;4(2):108-14
20139709
J Physiol. 2008 Apr 1;586(7):1791-801
18238816
J Biol Chem. 1998 Jul 31;273(31):19419-23
9677360
Cell Physiol Biochem. 2006;18(1-3):57-66
16914890
Cardiovasc Res. 2006 Jun 1;70(3):466-74
16564513
Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8792-7
11438691
Nature. 1998 Dec 17;396(6712):687-90
9872318
Br J Pharmacol. 2000 Dec;131(8):1503-6
11139424
EMBO J. 2003 Oct 15;22(20):5412-21
14532114
Science. 2002 Jan 18;295(5554):496-9
11799244
Neurobiol Dis. 2009 Jun;34(3):501-10
19344764
Neurobiol Dis. 2006 Oct;24(1):194-201
16916607
Circ Res. 2008 Dec 5;103(12):1451-7
19008479
Circ Res. 2006 Nov 10;99(10):1076-83
17053194
EMBO J. 2006 Feb 8;25(3):642-52
16437162
Epilepsy Res. 2007 Mar;73(3):245-9
17129708
Nature. 1996 Nov 7;384(6604):78-80
8900282
EMBO J. 1997 Sep 1;16(17):5472-9
9312006
J Cell Sci. 2004 Sep 1;117(Pt 19):4517-26
15316073
Nat Genet. 1998 Jan;18(1):25-9
9425895
Epilepsy Res. 2003 Feb;53(1-2):81-94
12576170
Neurology. 2008 Jul 15;71(3):177-83
18625963
J Biol Chem. 1999 Jul 23;274(30):21063-70
10409658
J Biol Chem. 2009 Feb 20;284(8):5250-6
19114714