Phosphatidylinositol 4,5-bisphosphate interactions with the HERG K(+) channel.
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.
Bian
Jin-Song
JS
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
McDonald
Thomas V
TV
D000818:Animals; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology*
D051638:Ether-A-Go-Go Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate