Investigating the Shaker-related K+ channel Kv1.1, the dysfunction of which is responsible for episodic ataxia 1 (EA1), at the functional and molecular level provides valuable understandings on normal channel dynamics, structural correlates underlying voltage-gating, and disease-causing mechanisms. Most studies focused on apparently functional amino acid residues composing voltage-gated K+ channels, neglecting the simplest ones. Glycine at position 311 of Kv1.1 is highly conserved both evolutionarily and within the Kv channel superfamily, is located in a region functionally relevant (the S4-S5 linker), and results in overt disease when mutated (p.G311D). By mutating the G311 residue to aspartate, we show here that the channel voltage-gating, activation, deactivation, inactivation, and window currents are markedly affected. In silico, modeling shows this glycine residue is strategically placed at one end of the linker helix which must be free to both bend and move past other portions of the protein during the channel’s opening and closing. This is befitting of a glycine residue as its small neutral side chain allows for movement unhindered by interaction with any other amino acid. Results presented reveal the crucial importance of a distinct glycine residue, within the S4-S5 linker, in the voltage-dependent electromechanical coupling that control channel gating.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Availability of data and material
Derived data supporting the findings of this study are available from the corresponding author CMD on request.
Episodic ataxia type 1
Potassium voltage-gated channel
- Kv1.1WT :
Wildtype potassium 1.1 voltage-gated channel
- Kv1.1G311D :
Mutant potassium voltage-gated channel
- Kv1.1WT/G311D :
Heteromeric wildtype and mutant potassium voltage-gated channel
Prediction of proteins in membrane
Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201
Begum R, Bakiri Y, Volynski KE, Kullmann DM (2016) Action potential broadening in a presynaptic channelopathy. Nat Commun 7:12102
Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Gallo Cassarino T, Bertoni M, Bordoli L, Schwede T (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252–W258
Bordoli L, Kiefer F, Arnold K, Benkert P, Battey J, Schwede T (2009) Protein structure homology modelling using SWISS-MODEL workspace. Nat Protoc 4:1–13
Brunetti O, Imbrici P, Botti FM, Pettorossi VE, D'Adamo MC, Valentino M, Zammit C, Mora M, Gibertini S, di Giovanni G, Muscat R, Pessia M (2012) Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature. Neurobiol Dis 47(3):310–321
Bu W, Liang Q, Zhi L, Maciunas L, Loll PJ, Eckenhoff RG, Covarrubias M (2018) Sites and functional consequence of Alkylphenol anesthetic binding to Kv1.2 channels. Mol Neurobiol 55:1692–1702
D’Adamo MC, Imbrici P, Sponcichetti F, Pessia M (1999) Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K+ channel function. FASEB J 13(11):1335–1345
D’Adamo MC, Liantonio A, Rolland JF, Pessia M, Imbrici P (2020) Kv1.1 channelopathies: pathophysiological mechanisms and therapeutic approaches. Int J Mol Sci 21(8):E2935
Hasan S, Bove C, Silvestri G, Mantuano E, Modoni A, Veneziano L, Hunter T, Hunter GJ, Pessia M, D’Adamo MC (2017) A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia. Sci Rep 7(4583):1–13
Hasan SM, D'Adamo MC (2010) Episodic ataxia type 1. Feb 9 [updated 2018 Nov 1]. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA) 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK25442/
Jensen MØ, Borhani DW, Lindorff-Larsen K, Maragakis P, Jogini V, Eastwood MP, Dror RO, Shaw DE (2010) Principles of conduction and hydrophobic gating in K+ channels. Proc Natl Acad Sci 107(13):5833–5838
Karalok ZS, Megaro A, Cenciarini M, Guven A, Hasan SM, Taskin BD, Imbrici P, Ceylaner S, Pessia M, D’Adamo MC (2018) Identification of a new de novo mutation underlying regressive episodic ataxia type I. Front Neurol 9:587
Kuba H, Yamada R, Ishiguro G, Adachi R (2015) Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity. Nat Commun 6:8815
Labro AJ, Raes AL, Grottesi A, Van HD, Sansom MS, Snyders DJ (2008) Kv channel gating requires a compatible S4-S5 linker and bottom part of S6, constrained by non-interacting residues. J Gen Physiol 132:667–680
Liang Q, Anderson WD, Jones ST, Souza CS, Hosoume JM, Treptow W, Covarrubias ML (2015) Positive allosteric modulation of Kv channels by sevoflurane: insights into the structural basis of inhaled anesthetic action. PLoS One 10(11):e0143363
Lomize MA, Pogozheva ID, Joo H, Mosberg HI, Lomize AL (2012) OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res 40:D370–D376
Lomize MA, Pogozheva ID, Mosberg HI (2011) Anisotropic solvent model of the lipid bilayer. 2. Energetics of insertion of small molecules, peptides, and proteins in membranes. J Chem Inf Model 51(4):930–946
Long SB, Campbell EB, MacKinnon R (2005) Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309:903–908
Pathak MM, Yarov-Yarovoy V, Agarwal G, Roux B, Barth P, Kohout S, Tombola F, Isacoff EY (2007) Closing in on the resting state of the shaker K+ channel. Neuron 56(1):124–140
Tomlinson SE, Tan SV, Kullmann DM, Griggs RC, Burke D, Hanna MG, Bostock H (2010) Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1. Brain 133(Pt 12):3530–3540
Tristán-Clavijo E, Scholl FG, Macaya A, Iglesias G, Rojas AM, Lucas M, Castellano A, Martinez-Mir A (2016) Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia. Mov Disord 11:1743–1748
Zerr P, Adelman JP, Maylie J (1998) Characterization of three episodic ataxia mutations in the human Kv1.1 potassium channel. FEBS Lett 431(3):461–464
Zhou L, Messing A, Chiu SY (1999) Determinants of excitability at transition zones in Kv1.1-deficient myelinated nerves. J Neurosci 19(14):5768–5781
Lorena Coretti is an Alfredo Leonardi’s foundation fellow.
This study is financially supported by the University of Malta Research, Innovation & Development Trust (RIDT) (Grant No. I20LU08, BooKind E20LG42) and of the United Arab Emirates University (Grants Nos. 31M452 and 31M468).
Conflict of interest
The authors declare that they have no conflicts of interest.
Procedures involving Xenopus laevis were in accordance with international standards of animal care, the Maltese Animal Welfare Act, and the NIH Guide for the Care and Use of Laboratory Animals. The procedure was approved by the local Veterinary Service Authority.
Consent to participate
Consent for publication
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the special issue on Channelopathies: from mutation to diseases in Pflügers Archiv—European Journal of Physiology
About this article
Cite this article
Hasan, S., Megaro, A., Cenciarini, M. et al. Electromechanical coupling of the Kv1.1 voltage-gated K+ channel is fine-tuned by the simplest amino acid residue in the S4-S5 linker. Pflugers Arch - Eur J Physiol (2020). https://doi.org/10.1007/s00424-020-02414-0
- Episodic ataxia type 1
- S4-S5 linker
- Xenopus laevis