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Int. J. Mol. Sci. 2018, 19(8), 2437; https://doi.org/10.3390/ijms19082437

The Insensitivity of TASK-3 K2P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure

1
Centro de Investigaciones Médicas (CIM), Programa de Investigación Asociativa en Cáncer Gástrico (PIA-CG), Escuela de Medicina, Universidad de Talca, Talca 3460000, Chile
2
Laboratorio de Fisiología Epitelial, Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique 1130000, Chile
*
Author to whom correspondence should be addressed.
Received: 17 July 2018 / Revised: 10 August 2018 / Accepted: 13 August 2018 / Published: 18 August 2018
(This article belongs to the Section Molecular Biophysics)
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Abstract

Two-pore domain K+ channels (K2P) display a characteristic extracellular cap structure formed by two M1-P1 linkers, the functional role of which is poorly understood. It has been proposed that the presence of the cap explains the insensitivity of K2P channels to several K+ channel blockers including tetraethylammonium (TEA). We have explored this hypothesis using mutagenesis and functional analysis, followed by molecular simulations. Our results show that the deletion of the cap structure of TASK-3 (TWIK-related acid-sensitive K+ channel) generates a TEA-sensitive channel with an IC50 of 11.8 ± 0.4 mM. The enhanced sensitivity to TEA displayed by the cap-less channel is also explained by the presence of an extra tyrosine residue at position 99. These results were corroborated by molecular simulation analysis, which shows an increased stability in the binding of TEA to the cap-less channel when a ring of four tyrosine is present at the external entrance of the permeation pathway. Consistently, Y99A or Y205A single-residue mutants generated in a cap-less channel backbone resulted in TASK-3 channels with low affinity to external TEA. View Full-Text
Keywords: TASK-3 channels; two-pore domain channel; TEA TASK-3 channels; two-pore domain channel; TEA
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Concha, G.; Bustos, D.; Zúñiga, R.; Catalán, M.A.; Zúñiga, L. The Insensitivity of TASK-3 K2P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure. Int. J. Mol. Sci. 2018, 19, 2437.

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