A Common Structural Component for β-Subunit Mediated Modulation of Slow Inactivation in Different KV Channels

• Main Authors: Nathalie Strutz-Seebohm, Ulrike Henrion, Nicole Schmitt, Eric Schulze-Bahr, Guiscard Seebohm
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2013-06-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Ion channel; Modulation; Gating; Conduction; β-subunit
• Online Access: http://www.karger.com/Article/FullText/350115
• ISSN: 1015-8987; 1421-9778

Background/Aims: Potassium channels are tetrameric proteins providing potassium selective passage through lipid embedded proteinaceous pores with highest fidelity. The selectivity results from binding to discrete potassium binding sites and stabilization of a hydrated potassium ion in a central internal cavity. The four potassium binding sites, generated by the conserved TTxGYGD signature sequence are formed by the backbone carbonyls of the amino acids TXGYG. Residues KV1.5-Val481, KV4.3-Leu368 and KV7.1- Ile 313 represent the amino acids in the X position of the respective channels. Methods: Here, we study the impact of these residues on ion selectivity, permeation and inactivation kinetics as well as the modulation by β-subunits using site-specific mutagenesis, electrophysiological analyses and molecular dynamics simulations. Results: We identify this position as key in modulation of slow inactivation by structurally dissimilar β-subunits in different KV channels. Conclusion: We propose a model in which structural changes accompanying activation and β-subunit modulation allosterically constrain the backbone carbonyl oxygen atoms via the side chain of the respective X-residue in the signature sequence to reduce conductance during slow inactivation.