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J. Biol. Chem., Vol. 279, Issue 49, 50726-50734, December 3, 2004

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Regulation of Cardiac I_Ks Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate^*

Wei-Guang Ding, Futoshi Toyoda, and Hiroshi Matsuura

From the Department of Physiology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan

Regulation of the slowly activating component of delayed rectifier K⁺ current (I_Ks) by membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns-(4,5)P₂) was examined in guinea pig atrial myocytes using the whole-cell patch clamp method. I_Ks was elicited by depolarizing voltage steps given from a holding potential of –50 mV, and the effect of various test reagents on I_Ks was assessed by measuring the amplitude of tail current elicited upon return to the holding potential following a 2-s depolarization to +30 mV. Intracellular application of 50 µM wortmannin through a recording pipette evoked a progressive increase in I_Ks over a 10–15-min period to 208.5 ± 14.6% (n = 9) of initial magnitude obtained shortly after rupture of the patch membrane. Intracellular application of anti-PtdIns(4,5)P₂ monoclonal antibody also increased the amplitude of I_Ks to 198.4 ± 19.9% (n = 5). In contrast, intracellular loading with exogenous PtdIns(4,5)P₂ at 10 and 100 µM produced a marked decrease in the amplitude of I_Ks to 54.3 ± 3.8% (n = 5) and 44.8 ± 8.2% (n = 5), respectively. Intracellular application of neomycin (50 µM) or aluminum (50 µM) evoked an increase in the amplitude of I_Ks to 161.0 ± 13.5% (n = 4) and 150.0 ± 8.2% (n = 4), respectively. These results strongly suggest that I_Ks channel is inhibited by endogenous membrane PtdIns(4,5)P₂ through the electrostatic interaction with the negatively charged head group on PtdIns(4,5)P₂. Potentiation of I_Ks by P2Y receptor stimulation with 50 µM ATP was almost totally abolished when PtdIns(4,5)P₂ was included in the pipette solution, suggesting that depletion of membrane PtdIns(4,5)P₂ is involved in the potentiation of I_Ks by P2Y receptor stimulation. Thus, membrane PtdIns(4,5)P₂ may act as an important physiological regulator of I_Ks in guinea pig atrial myocytes.

Received for publication, August 16, 2004 , and in revised form, September 10, 2004.

^* This work was supported by Grants-in-aid for Scientific Research 13670042 and 15590184 (to H. M.) from Japan Society for the Promotion of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-77-548-2152; Fax: 81-77-548-2348; E-mail: ding{at}belle.shiga-med.ac.jp.

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