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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gα_o is necessary for muscarinic regulation of Ca~(2+) channels in mouse heart
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Gα_o is necessary for muscarinic regulation of Ca~(2+) channels in mouse heart

机译：Gα_o是毒蕈碱调节小鼠心脏Ca〜（2+）通道所必需的

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摘要

Heterotrimeric G proteins, composed of Gα and Gβγ subunits, transmit signals from cell surface receptors to cellular effector enzymes and ion channels. The Gα_o protein is the most abundant Gα subtype in the nervous system, but it is also found in the heart. Its function is not completely known, although it is required for regulation of N-type Ca~(2+) channels in GH_3 cells and also interacts with GAP43, a major protein in growth cones, suggesting a role in neuronal pathfinding. To analyze the function of Gα_o, we have generated mice lacking both isoforms of Gα_o by homologous recombination. Surprisingly, the nervous system is grossly intact, despite the fact that Gα_o makes up 0.2-0.5% of brain particulate protein and 10% of the growth cone membrane. The Gα_o-/- mice do suffer tremors and occasional seizures, but there is no obvious histologic abnormality in the nervous system. In contrast, Gα_o-/- mice have a clear and specific defect in ion channel regulation in the heart. Normal muscarinic regulation of L-type calcium channels in ventricular myocytes is absent in the mutant mice. The L-type calcium channel responds normally to isoproterenol, but there is no evident muscarinic inhibition. Muscarinic regulation of atrial K~+ channels is normal, as is the electrocardiogram. The levels of other Gα subunits (Gα_s, Gα_q, and Gα_i) are unchanged in the hearts of Gα_o-/- mice, but the amount of Gβγ is decreased. Whichever subunit, Gα_o or Gβγ, carries the signal forward, these studies show that muscarinic inhibition of L-type Ca~(2+) channels requires coupling of the muscarinic receptor to Gα_o. Other cardiac Gα subunits cannot substitute.
机译：由Gα和Gβγ亚基组成的异三聚体G蛋白将信号从细胞表面受体传递到细胞效应酶和离子通道。 Gα_o蛋白是神经系统中最丰富的Gα亚型，但也存在于心脏中。尽管它的功能是调节GH_3细胞中N型Ca〜（2+）通道所必需的，并且还与生长锥中的主要蛋白质GAP43相互作用，但它的功能尚不完全清楚，这提示其在神经元寻路中的作用。为了分析Gα_o的功能，我们通过同源重组产生了缺少两种Gα_o亚型的小鼠。出人意料的是，尽管Gα_o占大脑颗粒蛋白的0.2-0.5％和生长锥膜的10％，但神经系统却完好无损。 Gα_o-/-小鼠确实患有震颤和偶发性癫痫发作，但神经系统没有明显的组织学异常。相比之下，Gα_o-/-小鼠在心脏离子通道调节方面存在明显的特异性缺陷。在突变小鼠中，心室肌细胞中L型钙通道的正常毒蕈碱调节作用不存在。 L型钙通道通常对异丙肾上腺素有反应，但没有明显的毒蕈碱抑制作用。心房K〜+通道的毒蕈碱调节正常，心电图也正常。 Gα_o-/-小鼠心脏中其他Gα亚基（Gα_s，Gα_q和Gα_i）的水平保持不变，但Gβγ的数量减少。无论哪个亚基，Gα_o或Gβγ都向前传递信号，这些研究表明毒蕈碱抑制L型Ca〜（2+）通道需要毒蕈碱受体与Gα_o偶联。其他心脏Gα亚基不能替代。

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