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Phosphatidylinositol 4,5-bisphosphate interactions with the HERG K+ channel

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Abstract

Regulation of ion channel activity plays a central role in controlling heart rate, rhythm, and contractility responses to cardiovascular demands. Dynamic beat-to-beat regulation of ion channels is precisely adjusted by autonomic stimulation of cardiac G protein-coupled receptors. The rapidly activating delayed rectifier K+ current (I Kr) is produced by the channel that is encoded by human ether-a-gogo-related gene (HERG) and is essential for the proper repolarization of the cardiac myocyte at the end of each action potential. Reduction of I Kr via HERG mutations or drug block can lead to lethal cardiac tachyarrhythmias. Autonomic regulation of HERG channels is an area of active investigation with the emerging picture of a complex interplay of signal transduction events, including kinases, second messengers, and protein–protein interactions. A recently described pathway for regulation of HERG is through channel interaction with the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). Changes in cellular PIP2 concentrations may occur with Gq-coupled receptor activation. Here, we review the evidence for PIP2–HERG interactions, its potential biological significance, and unfilled gaps in our understanding of this regulatory mechanism.

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Acknowledgements

This work was supported by grants from the NHLBI and AHA to TVM and from the Singapore Biomedical Research Council to J-SB.

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  1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Jin-Song Bian

  2. Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Thomas V. McDonald

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Correspondence to Thomas V. McDonald.

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Bian, JS., McDonald, T.V. Phosphatidylinositol 4,5-bisphosphate interactions with the HERG K+ channel. Pflugers Arch - Eur J Physiol 455, 105–113 (2007). https://doi.org/10.1007/s00424-007-0292-5

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