An inactivation gate in the selectivity filter of KCNQ1 potassium channels.
Inactivation is an inherent property of most voltage-gated K(+) channels. While fast N-type inactivation has been analyzed in biophysical and structural details, the mechanisms underlying slow inactivation are yet poorly understood. Here, we characterized a slow inactivation mechanism in various KCNQ1 pore mutants, including L273F, which hinders entry of external Ba(2+) to its deep site in the pore and traps it by slowing its egress. Kinetic studies, molecular modeling, and dynamics simulations suggest that this slow inactivation involves conformational changes that converge to the outer carbonyl ring of the selectivity filter, where the backbone becomes less flexible. This mechanism involves acceleration of inactivation kinetics and enhancement of Ba(2+) trapping at elevated external K(+) concentrations. Hence, KCNQ1 slow inactivation considerably differs from C-type inactivation where vacation of K(+) from the filter was invoked. We suggest that trapping of K(+) at s(1) due to filter rigidity and hindrance of the dehydration-resolvation transition underlie the slow inactivation of KCNQ1 pore mutants.
Gibor
Gilad
G
Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
Yakubovich
Daniel
D
Rosenhouse-Dantsker
Avia
A
Peretz
Asher
A
Schottelndreier
Hella
H
Seebohm
Guiscard
G
Dascal
Nathan
N
Logothetis
Diomedes E
DE
Paas
Yoav
Y
Attali
Bernard
B
D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D015640:Ion Channel Gating / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D008954:Models, Biological; D009865:Oocytes / Q000502:physiology*; D012680:Sensitivity and Specificity; D014982:Xenopus laevis
D051657:KCNQ1 Potassium Channel
Nature. 2001 Jun 7;411(6838):657-61
11395760
Prog Biophys Mol Biol. 2006 Oct;92(2):185-208
16316679
J Physiol. 2001 Aug 15;535(Pt 1):65-81
11507158
J Gen Physiol. 2001 Sep;118(3):315-32
11524461
Nature. 2001 Nov 1;414(6859):37-42
11689935
Nature. 2001 Nov 1;414(6859):43-8
11689936
J Physiol. 2002 Dec 15;545(Pt 3):751-66
12482884
EMBO Rep. 2003 Jan;4(1):70-5
12524524
J Gen Physiol. 2003 Feb;121(2):111-24
12566539
Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
12824332
Biophys J. 2003 Jul;85(1):300-12
12829485
J Physiol. 2003 Oct 15;552(Pt 2):369-78
14561821
J Mol Biol. 2003 Nov 7;333(5):965-75
14583193
Biochemistry. 2004 May 4;43(17):4978-82
15109256
J Gen Physiol. 2004 Jul;124(1):83-102
15226366
J Gen Physiol. 1999 May;113(5):641-60
10228180
J Gen Physiol. 1999 Jun;113(6):819-36
10352033
Q Rev Biophys. 1998 Aug;31(3):239-95
10384687
EMBO J. 1999 Aug 2;18(15):4137-48
10428953
Nat Rev Neurosci. 2004 Dec;5(12):905-16
15550946
J Physiol. 2005 Mar 1;563(Pt 2):359-68
15649981
Structure. 2005 Apr;13(4):591-600
15837197
Nat Struct Mol Biol. 2005 May;12(5):454-9
15852022
Angew Chem Int Ed Engl. 2004 Aug 20;43(33):4265-77
15368373
J Gen Physiol. 1973 Jun;61(6):687-708
4541078
Science. 1990 Oct 26;250(4980):533-8
2122519
Science. 1990 Oct 26;250(4980):568-71
2122520
Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5092-5
2052588
Receptors Channels. 1993;1(1):61-71
8081712
Nature. 1996 Nov 7;384(6604):78-80
8900282
Nature. 1996 Nov 7;384(6604):80-3
8900283
Biophys J. 1997 Jan;72(1):163-74
8994601
Biophys J. 1997 Feb;72(2 Pt 1):708-19
9017198
Circulation. 1997 Sep 16;96(6):1733-6
9323054
J Gen Physiol. 1997 Nov;110(5):539-50
9348326
Science. 1998 Apr 3;280(5360):69-77
9525859
Biophys J. 1998 Apr;74(4):1808-20
9545043
J Physiol. 1998 Jul 1;510 ( Pt 1):37-45
9625865
Biophys J. 1998 Aug;75(2):785-92
9675180
J Membr Biol. 1998 Sep 1;165(1):19-35
9705979
Pflugers Arch. 1998 Dec;437(1):172-4
9817805
J Gen Physiol. 1998 Dec;112(6):651-63
9834138
J Gen Physiol. 1998 Dec;112(6):665-78
9834139
Biophys J. 1999 Jan;76(1 Pt 1):253-63
9876139
Biophys J. 2000 Jan;78(1):211-26
10620287
J Gen Physiol. 2000 Mar;115(3):269-72
10694255
J Gen Physiol. 2000 Aug;116(2):181-90
10919865
J Mol Biol. 2000 Sep 8;302(1):205-17
10964570
Neuron. 2000 Sep;27(3):573-83
11055439
J Gen Physiol. 2000 Nov;116(5):623-36
11055991
J Gen Physiol. 2001 Feb;117(2):149-63
11158167
Nat Neurosci. 2001 Mar;4(3):239-46
11224539
Nat Rev Neurosci. 2000 Oct;1(1):21-30
11252765
J Biol Chem. 2001 Apr 27;276(17):13600-5
11278406
Science. 2005 Aug 5;309(5736):897-903
16002581
Physiol Rev. 2005 Oct;85(4):1205-53
16183911
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15877-82
16247006
J Intern Med. 2006 Jan;259(1):59-69
16336514
Circ Res. 2006 Apr 28;98(8):1055-63
16556865
Nat Struct Mol Biol. 2006 Apr;13(4):319-22
16532008
Nat Struct Mol Biol. 2006 Apr;13(4):311-8
16532009
Biophys J. 2001 Aug;81(2):814-26
11463627