Dataset Information

The Insensitivity of TASK-3 K?P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure.

ABSTRACT: Two-pore domain K? channels (K?P) 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 K?P 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.

SUBMITTER: Concha G

PROVIDER: S-EPMC6121469 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Concha Guierdy G Bustos Daniel D Zúñiga Rafael R Catalán Marcelo A MA Zúñiga Leandro L

International journal of molecular sciences 20180818 8

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 TAS ...[more]

PMID: 30126179

Similar Datasets

Project description:Tandem pore domain acid-sensitive K+ (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction.NEW & NOTEWORTHY The role of tandem pore domain acid-sensitive K+ (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-? coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.

Dataset Information

The Insensitivity of TASK-3 K?P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets