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Am J Physiol Heart Circ Physiol (July 1, 2004). doi:10.1152/ajpheart.00120.2004
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Submitted on February 5, 2004
Accepted on June 28, 2004

Molecular analysis of Phosphatidyl Inositol 4,5-Bisphosphate Regulation of HERG/IKr

Jin-song Bian1, Anna Kagan2, and Thomas V. McDonald2*

1 Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore, Singapore; Department of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, USA
2 Department of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, USA

* To whom correspondence should be addressed. E-mail: mcdonald{at}aecom.yu.edu.

We have previously reported that cloned HERG K+ channels are regulated by changes in phosphatidylinositol 4,5-bisphosphate (PIP2) concentration. Here, we investigate the molecular determinants of PIP2 interactions with HERG channel protein. To establish the molecular nature of the PIP2/HERG interaction we examined a segment of the HERG C-terminus with a high concentration of positively charged amino acids (883-894) as a possible site of interaction with negatively charged PIP2. When we excised (D-HERG) or mutated this segment of HERG to the neutralize amino acid charge (M-HERG) the mutant channels produced current that was indistinguishable from wild type HERG. Elevating internal PIP2 however, no longer accelerated the activation kinetics of the mutant HERG. Moreover, PIP2-dependent hyperpolarizing shifts in the voltage-dependence of activation were abolished with both mutants. PIP2 effects on channel inactivation kinetics remained intact suggesting an uncoupling of inactivation and activation regulation by PIP2. The specific binding of radiolabeled PIP2 to both mutant channel proteins was nearly abolished. Stimulation of {alpha}1A adrenergic receptors produced a reduction in current amplitude of IKr, the current carried by ERG protein, from rabbit ventricular myocytes. The {alpha}-adrenergic-induced current reduction was accentuated by PKC blockers and also unmasked a depolarizing shift in the voltage dependence of activation, supporting the conclusion that receptor activation of phospholipase C results in PIP consumption that alters channel activity. These results support a physiological role for PIP2 regulation of IKr during autonomic stimulation and localize a site of interaction to the C-terminal tail of the HERG K+ channel.




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