Published online before print November 8, 2001, doi: 10.1161/hh2401.101375
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© 2001 American Heart Association, Inc.
Cellular Biology |
HERG K+ Channel Activity Is Regulated by Changes in Phosphatidyl Inositol 4,5-Bisphosphate
From the Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.
Correspondence to Thomas V. McDonald, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. E-mail mcdonald{at}aecom.yu.edu
Autonomic stimulation controls heart rate and myocardial excitability and may underlie the precipitation of both acquired and hereditary arrhythmias. Changes in phosphatidyl inositol bisphosphate (PIP2) concentration results from activation of several muscarinic and adrenergic receptors. We sought to investigate whether PIP2 changes could alter HERG K+ channel activity in a manner similar to that seen with inward rectifier channels. PIP2 (10 µmol/L) internally dialyzed increased the K+ current amplitude and shifted the voltage-dependence of activation in a hyperpolarizing direction. Elevated PIP2 accelerated activation and slowed inactivation kinetics. When 10 µmol/L PIP2 was applied to excised patches, no significant change in single channel conductance occurred, indicating that PIP2-dependent effects were primarily due to altered channel gating. PIP2 significantly attenuated the run-down of HERG channel activity that we normally observe after patch excision, suggesting that channel run-down is due, in part, to membrane depletion of PIP2. Inclusion of a neutralizing anti-PIP2 monoclonal antibody in whole cell pipette solution produced the opposite effects of PIP2. The physiological relevance of PIP2–HERG interactions is supported by our finding that phenylephrine reduced the K+ current density in cells coexpressing 
1A-receptor and HERG. The effects of -adrenergic stimulation, however, were prevented by excess PIP2 in internal solutions but not by internal Ca2+ buffering nor PKC inhibition, suggesting that the mechanism is due to G-protein–coupled receptor stimulation of PLC resulting in the consumption of endogenous PIP2. Thus, dynamic regulation of HERG K+ channels may be achieved via receptor-mediated changes in PIP2 concentrations.
Key Words: HERG • potassium channel • phospholipids • G-protein–coupled receptor
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