Gαi2, Gαi3 and Gα0 are all required for normal muscarinic inhibition of the cardiac calcium channels in nodal/atrial-like cultured cardiocytes

被引:24
|
作者
Ye, CP
Sowell, MO
Vassilev, PM
Milstone, DS
Mortensen, RM
机构
[1] Brigham & Womens Hosp, Dept Med, Div Endocrine Hypertens, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Dept Pathol, Div Vasc Res, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Boston, MA USA
关键词
G-proteins; calcium channels; isolated cardiocytes; signal transduction; muscarinic receptors; ES cells;
D O I
10.1006/jmcc.1999.1015
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The cardiac L-type calcium current (I-Ca.L) is an important regulator of myocardial contractility. It is activated by sympathetic stimulation and inhibited by parasympathetic activity via muscarinic acetylcholine receptors. Muscarinic inhibition of I-Ca.L occurs ria activation of pertussis toxin (PTX)-sensitive heterotrimeric G-proteins. Although recent studies have shown that expression of G(02) is important for this effect in adult mouse ventricular cells. two other PTX-sensitive G-proteins (C-t2 and G(i3)) are also expressed in cardiocytes and are activated. Their role in the regulation of I-Ca.l has not been examined. In addition. it is not known whether nodal/atrial cardiac cells use the same G-proteins. We show that gene inactivation of each of the three PTX-sensitive G(alpha)-proteins (alpha(i2). alpha(i3), and alpha(0)) affects muscarinic inhibition of cardiac I-Ca.L in embryonic stem (ES) cell-derived cardiocytes. Inactivation of either alpha(i2) or alpha(i3) markedly slows the time course of muscarinic inhibition of I-Ca.L, and in cells a here both alpha(i2), and alpha(i3), are inactivated the effects are not additive. We also establish an essential role for alpha(0) in this atrial/nodal-like cardiocyte system and show that alpha(0) acts proximal to NO generation. NO generation plays a critical role in I-Ca.L regulation since the nitric oxide synthase (NOS) antagonist. L-NMMA blocked the inhibition of I-Ca.L in WT and in alpha(i2)/alpha(i3)-null cells. In WT cells the NO generating agent SIN-1 inhibited I-Ca.L and the addition of carbachol resulted in faster inhibition. suggesting that pathways in addition to NO are also activated. This study shows that alpha(i2) and ri, play a critical role in the normal inhibition of carjiocyte I-Ca.L. Thus. all muscarinic receptor activated G-proteins )G(i2) G(i3) and G(0)) are necessary for normal inhibition and act through both NO and non-SO signaling pathways. (C) 1999 Academic Press.
引用
收藏
页码:1771 / 1781
页数:11
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