title: Initial steps of inactivation at the K+ channel selectivity filter.
abstract: K(+) efflux through K(+) channels can be controlled by C-type inactivation, which is thought to arise from a conformational change near the channel's selectivity filter. Inactivation is modulated by ion binding near the selectivity filter; however, the molecular forces that initiate inactivation remain unclear. We probe these driving forces by electrophysiology and molecular simulation of MthK, a prototypical K(+) channel. Either Mg(2+) or Ca(2+) can reduce K(+) efflux through MthK channels. However, Ca(2+), but not Mg(2+), can enhance entry to the inactivated state. Molecular simulations illustrate that, in the MthK pore, Ca(2+) ions can partially dehydrate, enabling selective accessibility of Ca(2+) to a site at the entry to the selectivity filter. Ca(2+) binding at the site interacts with K(+) ions in the selectivity filter, facilitating a conformational change within the filter and subsequent inactivation. These results support an ionic mechanism that precedes changes in channel conformation to initiate inactivation.
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thomson
authors.forename: Florian T
authors.initials: FT
authors.lastname: Heer
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Smith
authors.forename: Eunan
authors.initials: E
authors.lastname: Hendron
authors.forename: Simon
authors.initials: S
authors.lastname: Bernèche
authors.forename: Brad S
authors.initials: BS
authors.lastname: Rothberg
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002413:Cations, Divalent / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D007477:Ions / Q000378:metabolism; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D018892:Proton-Motive Force; D013816:Thermodynamics
chemical_list: D002413:Cations, Divalent; D007477:Ions; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011188:Potassium; D002118:Calcium
keywords: calcium; dynamics; energetics; gating; permeation
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2151-6
references.pmid: 17287352
references.citation: Biophys J. 2012 Sep 19;103(6):1198-207
references.pmid: 22995492
references.citation: Biophys J. 1994 Apr;66(4):1068-75
references.pmid: 8038379
references.citation: J Gen Physiol. 2005 Mar;125(3):273-86
references.pmid: 15738049
references.citation: J Biol Chem. 2006 Jul 28;281(30):21131-21138
references.pmid: 16728395
references.citation: J Gen Physiol. 2005 Apr;125(4):413-26
references.pmid: 15795311
references.citation: Curr Opin Struct Biol. 2001 Apr;11(2):236-42
references.pmid: 11297934
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17684-9
references.pmid: 21997217
references.citation: J Gen Physiol. 2006 Aug;128(2):203-17
references.pmid: 16847099
references.citation: Structure. 2012 Dec 5;20(12):2038-47
references.pmid: 23085076
references.citation: Recept Channels. 1993;1(1):61-71
references.pmid: 8081712
references.citation: J Chem Theory Comput. 2013 Apr 9;9(4):1885-1895
references.pmid: 23814508
references.citation: J Gen Physiol. 2013 Feb;141(2):151-60
references.pmid: 23319730
references.citation: Nature. 2002 May 30;417(6888):515-22
references.pmid: 12037559
references.citation: J Gen Physiol. 1973 Jun;61(6):687-708
references.pmid: 4541078
references.citation: J Comput Chem. 2004 Aug;25(11):1400-15
references.pmid: 15185334
references.citation: Neuron. 1996 Apr;16(4):859-67
references.pmid: 8608004
references.citation: J Gen Physiol. 2011 Dec;138(6):571-80
references.pmid: 22124115
references.citation: Chem Rev. 2003 Mar;103(3):773-88
references.pmid: 12630852
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):1062-9
references.pmid: 17922012
references.citation: Biophys J. 1996 Dec;71(6):3157-66
references.pmid: 8968586
references.citation: Nature. 2001 Nov 1;414(6859):73-7
references.pmid: 11689945
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8644-8
references.pmid: 12837936
references.citation: J Gen Physiol. 1991 Jul;98(1):163-81
references.pmid: 1940847
references.citation: Phys Rev A Gen Phys. 1985 Mar;31(3):1695-1697
references.pmid: 9895674
references.citation: Neuron. 1995 Oct;15(4):951-60
references.pmid: 7576643
references.citation: J Gen Physiol. 2010 Nov;136(5):569-79
references.pmid: 20937694
references.citation: Nature. 2010 Jul 8;466(7303):203-8
references.pmid: 20613835
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1075-80
references.pmid: 19144926
references.citation: Nat Struct Mol Biol. 2009 Dec;16(12):1252-8
references.pmid: 19915587
references.citation: Nat Struct Mol Biol. 2006 Apr;13(4):311-8
references.pmid: 16532009
references.citation: Biophys J. 1994 Apr;66(4):1061-7
references.pmid: 8038378
references.citation: Structure. 2011 Jan 12;19(1):70-9
references.pmid: 21220117
references.citation: J Struct Biol. 2010 Aug;171(2):231-7
references.pmid: 20371380
references.citation: Nature. 2002 May 30;417(6888):523-6
references.pmid: 12037560
references.citation: J Comput Chem. 2008 Aug;29(11):1859-65
references.pmid: 18351591
references.citation: J Gen Physiol. 2007 Feb;129(2):109-20
references.pmid: 17261840
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11631-5
references.pmid: 7526400
references.citation: Biophys J. 2008 Nov 1;95(9):4205-16
references.pmid: 18641071
references.citation: J Gen Physiol. 2010 May;135(5):509-26
references.pmid: 20421375
references.citation: Science. 1996 Feb 2;271(5249):653-6
references.pmid: 8571129
references.citation: Nat Struct Mol Biol. 2010 Aug;17(8):1019-23
references.pmid: 20676101
references.citation: Structure. 2005 Apr;13(4):591-600
references.pmid: 15837197
references.citation: Biophys J. 2011 May 18;100(10):2387-93
references.pmid: 21575572
references.citation: J Phys Chem B. 2006 Sep 21;110(37):18553-9
references.pmid: 16970483
references.citation: Biophys J. 1996 Feb;70(2):798-805
references.pmid: 8789096
references.citation: Nat Struct Mol Biol. 2013 Feb;20(2):159-66
references.pmid: 23262489
references.citation: Neuron. 1991 Oct;7(4):547-56
references.pmid: 1931050
references.citation: Biophys J. 2002 Mar;82(3):1681-4
references.pmid: 11898796
references.citation: J Gen Physiol. 1988 Jul;92(1):67-86
references.pmid: 3171535