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Circulation Research. 2002
Published online before print July 18, 2002, doi: 10.1161/01.RES.0000029971.60214.49
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Submitted on March 13, 2001
Revised on July 8, 2002
Accepted on July 8, 2002

{alpha}1-Adrenoceptor--Mediated Breakdown of Phosphatidylinositol 4,5-Bisphosphate Inhibits Pinacidil-Activated ATP-Sensitive K+ Currents in Rat Ventricular Myocytes

Tetsuya Haruna ; Hidetada Yoshida ; Tomoe Y. Nakamura ; Lai-Hua Xie ; Hideo Otani ; Tomonori Ninomiya ; Makoto Takano ; William A. Coetzee ; and Minoru Horie *

From the Departments of Cardiovascular Medicine (T.H., H.Y., H.O., T.N., M.H.) and Physiology and Biophysics (L.-H.X., M.T.), Kyoto University Graduate School of Medicine, Kyoto, Japan, and Pediatric Cardiology (T.Y.N., W.A.C.), NYU School of Medicine, New York, NY.

* To whom correspondence should be addressed. E-mail: horie{at}kuhp.kyoto-u.ac.jp.

Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates ATP-sensitive K+ (KATP) channel activity. Because phospholipase C (PLC) hydrolyzes membrane-bound PIP2, which in turn may potentially decrease KATP channel activity, we investigated the effects of the {alpha}1-adrenoceptor--Gq--PLC signal transduction axis on pinacidil-activated KATP channel activity in adult rat and neonatal mouse ventricular myocytes. The {alpha}1-adrenoceptor agonist methoxamine (MTX) reversibly inhibited the pinacidil-activated KATP current in a concentration-dependent manner (IC50 20.9±6.6 µmol/L). This inhibition did not occur when the specific {alpha}1-adrenoceptor antagonist, prazosin, was present. An involvement of G proteins is suggested by the ability of GDPßS to prevent this response. Blockade of PLC by U-73122 (2 µmol/L) or neomycin (2 mmol/L) attenuated the MTX-induced inhibition of KATP channel activity. In contrast, the MTX response was unaffected by protein kinase C inhibition or stimulation by H-7 (100 µmol/L) or phorbol 12,13-didecanoate. The MTX-induced inhibition became irreversible in the presence of wortmannin (20 µmol/L), an inhibitor of phosphatidylinositol-4 kinase, which is expected to prevent membrane PIP2 replenishment. In excised inside-out patch membranes, pinacidil induced a significantly rightward shift of ATP sensitivity of the channel. This phenomenon was reversed by pretreatment of myocytes with MTX. Direct visualization of PIP2 subcellular distribution using a PLC{delta} pleckstrin homology domain--green fluorescent protein fusion constructs revealed reversible translocation of green fluorescent protein fluorescence from the membrane to the cytosol after {alpha}1-adrenoceptor stimulation. Our data demonstrate that {alpha}1-adrenoceptor stimulation reduces the membrane PIP2 level, which in turn inhibits pinacidil-activated KATP channels.
Key words: ATP-sensitive K+ channels • phosphatidylinositol 4,5-bisphosphate • {alpha}1-adrenoceptors




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