title: An inactivation gate in the selectivity filter of KCNQ1 potassium channels.
abstract: 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.
authors: Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
authors: Gilad
authors: G
authors: Gibor
authors: Daniel
authors: D
authors: Yakubovich
authors: Avia
authors: A
authors: Rosenhouse-Dantsker
authors: Asher
authors: A
authors: Peretz
authors: Hella
authors: H
authors: Schottelndreier
authors: Guiscard
authors: G
authors: Seebohm
authors: Nathan
authors: N
authors: Dascal
authors: Diomedes E
authors: DE
authors: Logothetis
authors: Yoav
authors: Y
authors: Paas
authors: Bernard
authors: B
authors: Attali
mesh_terms: 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
chemical_list: D051657:KCNQ1 Potassium Channel
references: Nature. 2001 Jun 7;411(6838):657-61
references: 11395760
references: Prog Biophys Mol Biol. 2006 Oct;92(2):185-208
references: 16316679
references: J Physiol. 2001 Aug 15;535(Pt 1):65-81
references: 11507158
references: J Gen Physiol. 2001 Sep;118(3):315-32
references: 11524461
references: Nature. 2001 Nov 1;414(6859):37-42
references: 11689935
references: Nature. 2001 Nov 1;414(6859):43-8
references: 11689936
references: J Physiol. 2002 Dec 15;545(Pt 3):751-66
references: 12482884
references: EMBO Rep. 2003 Jan;4(1):70-5
references: 12524524
references: J Gen Physiol. 2003 Feb;121(2):111-24
references: 12566539
references: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references: 12824332
references: Biophys J. 2003 Jul;85(1):300-12
references: 12829485
references: J Physiol. 2003 Oct 15;552(Pt 2):369-78
references: 14561821
references: J Mol Biol. 2003 Nov 7;333(5):965-75
references: 14583193
references: Biochemistry. 2004 May 4;43(17):4978-82
references: 15109256
references: J Gen Physiol. 2004 Jul;124(1):83-102
references: 15226366
references: J Gen Physiol. 1999 May;113(5):641-60
references: 10228180
references: J Gen Physiol. 1999 Jun;113(6):819-36
references: 10352033
references: Q Rev Biophys. 1998 Aug;31(3):239-95
references: 10384687
references: EMBO J. 1999 Aug 2;18(15):4137-48
references: 10428953
references: Nat Rev Neurosci. 2004 Dec;5(12):905-16
references: 15550946
references: J Physiol. 2005 Mar 1;563(Pt 2):359-68
references: 15649981
references: Structure. 2005 Apr;13(4):591-600
references: 15837197
references: Nat Struct Mol Biol. 2005 May;12(5):454-9
references: 15852022
references: Angew Chem Int Ed Engl. 2004 Aug 20;43(33):4265-77
references: 15368373
references: J Gen Physiol. 1973 Jun;61(6):687-708
references: 4541078
references: Science. 1990 Oct 26;250(4980):533-8
references: 2122519
references: Science. 1990 Oct 26;250(4980):568-71
references: 2122520
references: Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5092-5
references: 2052588
references: Receptors Channels. 1993;1(1):61-71
references: 8081712
references: Nature. 1996 Nov 7;384(6604):78-80
references: 8900282
references: Nature. 1996 Nov 7;384(6604):80-3
references: 8900283
references: Biophys J. 1997 Jan;72(1):163-74
references: 8994601
references: Biophys J. 1997 Feb;72(2 Pt 1):708-19
references: 9017198
references: Circulation. 1997 Sep 16;96(6):1733-6
references: 9323054
references: J Gen Physiol. 1997 Nov;110(5):539-50
references: 9348326
references: Science. 1998 Apr 3;280(5360):69-77
references: 9525859
references: Biophys J. 1998 Apr;74(4):1808-20
references: 9545043
references: J Physiol. 1998 Jul 1;510 ( Pt 1):37-45
references: 9625865
references: Biophys J. 1998 Aug;75(2):785-92
references: 9675180
references: J Membr Biol. 1998 Sep 1;165(1):19-35
references: 9705979
references: Pflugers Arch. 1998 Dec;437(1):172-4
references: 9817805
references: J Gen Physiol. 1998 Dec;112(6):651-63
references: 9834138
references: J Gen Physiol. 1998 Dec;112(6):665-78
references: 9834139
references: Biophys J. 1999 Jan;76(1 Pt 1):253-63
references: 9876139
references: Biophys J. 2000 Jan;78(1):211-26
references: 10620287
references: J Gen Physiol. 2000 Mar;115(3):269-72
references: 10694255
references: J Gen Physiol. 2000 Aug;116(2):181-90
references: 10919865
references: J Mol Biol. 2000 Sep 8;302(1):205-17
references: 10964570
references: Neuron. 2000 Sep;27(3):573-83
references: 11055439
references: J Gen Physiol. 2000 Nov;116(5):623-36
references: 11055991
references: J Gen Physiol. 2001 Feb;117(2):149-63
references: 11158167
references: Nat Neurosci. 2001 Mar;4(3):239-46
references: 11224539
references: Nat Rev Neurosci. 2000 Oct;1(1):21-30
references: 11252765
references: J Biol Chem. 2001 Apr 27;276(17):13600-5
references: 11278406
references: Science. 2005 Aug 5;309(5736):897-903
references: 16002581
references: Physiol Rev. 2005 Oct;85(4):1205-53
references: 16183911
references: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15877-82
references: 16247006
references: J Intern Med. 2006 Jan;259(1):59-69
references: 16336514
references: Circ Res. 2006 Apr 28;98(8):1055-63
references: 16556865
references: Nat Struct Mol Biol. 2006 Apr;13(4):319-22
references: 16532008
references: Nat Struct Mol Biol. 2006 Apr;13(4):311-8
references: 16532009
references: Biophys J. 2001 Aug;81(2):814-26
references: 11463627