A Constricted Opening in Kir Channels Does Not Impede Potassium Conduction

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jun 17

PMID 32541684

Citations 11

Authors

Katrina A Black

Sitong He

Ruitao Jin

David M Miller

Jani R Bolla

Oliver B Clarke

Paul Johnson

Monique Windley

Christopher J Burns

Adam P Hill

Derek Laver

Carol V Robinson

Brian J Smith

Jacqueline M Gulbis

Affiliations

Soon will be listed here.

Abstract

The canonical mechanistic model explaining potassium channel gating is of a conformational change that alternately dilates and constricts a collar-like intracellular entrance to the pore. It is based on the premise that K ions maintain a complete hydration shell while passing between the transmembrane cavity and cytosol, which must be accommodated. To put the canonical model to the test, we locked the conformation of a Kir K channel to prevent widening of the narrow collar. Unexpectedly, conduction was unimpaired in the locked channels. In parallel, we employed all-atom molecular dynamics to simulate K ions moving along the conduction pathway between the lower cavity and cytosol. During simulations, the constriction did not significantly widen. Instead, transient loss of some water molecules facilitated K permeation through the collar. The low free energy barrier to partial dehydration in the absence of conformational change indicates Kir channels are not gated by the canonical mechanism.

Citing Articles

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References

Thuringer D, Chanteloup G, Boucher J, Pernet N, Boudesco C, Jego G . Modulation of the inwardly rectifying potassium channel Kir4.1 by the pro-invasive miR-5096 in glioblastoma cells. Oncotarget. 2017; 8(23):37681-37693. PMC: 5514940. DOI: 10.18632/oncotarget.16949. View

Reichold M, Zdebik A, Lieberer E, Rapedius M, Schmidt K, Bandulik S . KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci U S A. 2010; 107(32):14490-5. PMC: 2922599. DOI: 10.1073/pnas.1003072107. View

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

Bavro V, De Zorzi R, Schmidt M, Muniz J, Zubcevic L, Sansom M . Structure of a KirBac potassium channel with an open bundle crossing indicates a mechanism of channel gating. Nat Struct Mol Biol. 2012; 19(2):158-63. PMC: 3272479. DOI: 10.1038/nsmb.2208. View

Sicca F, Ambrosini E, Marchese M, Sforna L, Servettini I, Valvo G . Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy. Sci Rep. 2016; 6:34325. PMC: 5039625. DOI: 10.1038/srep34325. View

Im W, Roux B . Ions and counterions in a biological channel: a molecular dynamics simulation of OmpF porin from Escherichia coli in an explicit membrane with 1 M KCl aqueous salt solution. J Mol Biol. 2002; 319(5):1177-97. DOI: 10.1016/S0022-2836(02)00380-7. View

Sicca F, Imbrici P, DAdamo M, Moro F, Bonatti F, Brovedani P . Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K+ channel Kir4.1. Neurobiol Dis. 2011; 43(1):239-47. DOI: 10.1016/j.nbd.2011.03.016. View

Rapedius M, Soom M, Shumilina E, Schulze D, Schonherr R, Kirsch C . Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. J Biol Chem. 2005; 280(35):30760-7. DOI: 10.1074/jbc.M503503200. View

Sun C, Zou M, Li L, Li D, Ma Y, Xia W . Association study between inwardly rectifying potassium channels 2.1 and 4.1 and autism spectrum disorders. Life Sci. 2018; 213:183-189. DOI: 10.1016/j.lfs.2018.10.012. View

10.

Allen T, Andersen O, Roux B . Ion permeation through a narrow channel: using gramicidin to ascertain all-atom molecular dynamics potential of mean force methodology and biomolecular force fields. Biophys J. 2006; 90(10):3447-68. PMC: 1440729. DOI: 10.1529/biophysj.105.077073. View

11.

Fan C, Kuhn M, Mbiol A, Groome J, Winston V, Biskup S . Kir2.2 p.Thr140Met: a genetic susceptibility to sporadic periodic paralysis. Acta Myol. 2019; 37(3):193-203. PMC: 6390110. View

12.

Hansen S, Tao X, MacKinnon R . Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature. 2011; 477(7365):495-8. PMC: 3324908. DOI: 10.1038/nature10370. View

13.

. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr. 1994; 50(Pt 5):760-3. DOI: 10.1107/S0907444994003112. View

14.

Swale D, Kharade S, Denton J . Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics. Curr Opin Pharmacol. 2014; 15:7-15. PMC: 4097192. DOI: 10.1016/j.coph.2013.11.002. View

15.

Webb B, Sali A . Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics. 2016; 54:5.6.1-5.6.37. PMC: 5031415. DOI: 10.1002/cpbi.3. View

16.

Nishida M, Cadene M, Chait B, MacKinnon R . Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J. 2007; 26(17):4005-15. PMC: 1994128. DOI: 10.1038/sj.emboj.7601828. View

17.

Wilkens C, Aldrich R . State-independent block of BK channels by an intracellular quaternary ammonium. J Gen Physiol. 2006; 128(3):347-64. PMC: 2151567. DOI: 10.1085/jgp.200609579. View

18.

Allen T, Andersen O, Roux B . Molecular dynamics - potential of mean force calculations as a tool for understanding ion permeation and selectivity in narrow channels. Biophys Chem. 2006; 124(3):251-67. DOI: 10.1016/j.bpc.2006.04.015. View

19.

Su Z, Brown E, Wang W, MacKinnon R . Novel cell-free high-throughput screening method for pharmacological tools targeting K+ channels. Proc Natl Acad Sci U S A. 2016; 113(20):5748-53. PMC: 4878532. DOI: 10.1073/pnas.1602815113. View

20.

Varma S, Rempe S . Coordination numbers of alkali metal ions in aqueous solutions. Biophys Chem. 2006; 124(3):192-9. DOI: 10.1016/j.bpc.2006.07.002. View