α1-adrenoceptor-mediated breakdown of phosphatidylinositol 4,5-bisphosphate inhibits pinacidil-activated ATP-Sensitive K+ currents in rat ventricular myocytes

被引:26
作者
Haruna, T
Yoshida, H
Nakamura, TY
Xie, LH
Otani, H
Ninomiya, T
Takano, M
Coetzee, WA
Horie, M
机构
[1] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Sakyo Ku, Kyoto 6068507, Japan
[2] Kyoto Univ, Grad Sch Med, Dept Physiol & Biophys, Sakyo Ku, Kyoto 6068507, Japan
[3] NYU, Sch Med, Dept Pediat Cardiol, New York, NY USA
关键词
ATP-sensitive K+ channels; phosphatidylinositol 4,5-bisphosphate; alpha(1)-adrenoceptors;
D O I
10.1161/01.RES.0000029971.60214.49
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Phosphatidylinositol 4,5-bisphosphate (PIP2) stimulates ATP-sensitive K+ (K-ATP) channel activity. Because phospholipase C (PLC) hydrolyzes membrane-bound PIP2, which in turn may potentially decrease K-ATP channel activity, we investigated the effects of the alpha(1)-adrenoceptor-G(q)-PLC signal transduction axis on pinacidil-activated K-ATP channel activity in adult rat and neonatal mouse ventricular myocytes. The alpha(1)-adrenoceptor agonist methoxamine (MTX) reversibly inhibited the pinacidil-activated K-ATP current in a concentration-dependent manner (IC50 20.9+/-6.6 mumol/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 GDPbetaS to prevent this response. Blockade of PLC by U-73122 (2 mumol/L) or neomycin (2 mmol/L) attenuated the MTX-induced inhibition of K-ATP channel activity. In contrast, the MTX response was unaffected by protein kinase C inhibition or stimulation by H-7 (100 mumol/L) or phorbol 12,13-didecanoate. The MTX-induced inhibition became irreversible in the presence of wortmannin (20 mumol/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 PLCdelta 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 K-ATP channels.
引用
收藏
页码:232 / 239
页数:8
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