Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through β2-adrenoceptors
Cardioprotection specific for the G protein Gi2 in chronic adrenergic signaling through β2-adrenoceptors
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DOI：
10.1073/pnas.1936026100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Herzig, S
中科院分区：
文献类型：
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作者：
Foerster, K;Groner, F;Herzig, S
β-肾上腺素受体的两种亚型，β(1) 和β(2)，介导心脏儿茶酚胺作用。这两种类型有质的不同，例如，在 G 蛋白偶联和钙通道刺激方面。与过度表达β(1)-肾上腺素受体的小鼠不同，过度表达人类β(2)-肾上腺素受体的转基因小鼠能够以高表达水平存活。我们研究了抑制性 G(i) 蛋白（已知可被 β(2) 而非 β(1) 肾上腺素受体激活）对转基因小鼠中人类 β(2) 肾上腺素受体过度表达的慢性影响的作用。这些小鼠与 Galpha(i2) 小鼠杂交，Galpha(i2) 是一种功能重要的心脏 G(i) α 亚基，通过靶向基因删除而失活。 β(2)-肾上腺素受体转基因小鼠的存活率因 Galpha(i2) 杂合失活而降低。纯合基因敲除/β(2)-肾上腺素受体转基因小鼠在出生后4天内死亡。与β(2)-肾上腺素受体转基因小鼠相比，杂合基因敲除/β(2)-肾上腺素受体转基因小鼠出现更明显的心脏肥大和更早的心力衰竭。在杂合基因敲除/β(2)-肾上腺素受体转基因小鼠中，单一钙通道活性受到强烈抑制。在这些小鼠的心肌细胞中，百日咳毒素体外处理完全恢复了通道活性，并增强了纯合 Galpha(i2) 敲除动物细胞中的通道活性。所有 Galpha(i2) 敲除小鼠品系的心脏 Galpha(i3) 蛋白均增加。我们的结果表明，Galpha(i2) 在过度表达的 β(2)-肾上腺素受体的慢性信号传导中发挥重要的保护作用，从而导致生存期延长和心脏病理学延迟。然而，β(2)-肾上腺素受体过度表达导致钙通道活性降低是由于不同的百日咳毒素敏感途径，最有可能是通过 Galpha(i3)。该结果表明，β(2)-肾上腺素受体的亚型特异性信号传导在 G(i) 水平上功能性分叉，导致不同的效应，具体取决于 Galpha 亚型。
Two subtypes of beta-adrenoceptors, beta(1) and beta(2), mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human beta(2)-adrenoceptors survive high-expression levels, unlike mice overexpressing beta(1)-adrenoceptors. We examined the role of inhibitory G(i) proteins, known to be activated by beta(2)- but not beta(1)-adrenoceptors, on the chronic effects of human beta(2)-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where Galpha(i2), a functionally important cardiac G(i) alpha-subunit, was inactivated by targeted gene deletion. Survival of beta(2)-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of Galpha(i2). Homozygous knockout/beta(2)-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout/beta(2)-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with beta(2)-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout/beta(2)-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous Galpha(i2) knockout animals. Cardiac Galpha(i3) protein was increased in all Galpha(i2) knockout mouse strains. Our results demonstrate that Galpha(i2) takes an essential protective part in chronic signaling of overexpressed beta(2)-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by beta(2)-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by Galpha(i3). This result indicates that subtype-specific signaling of beta(2)-adrenoreceptor functionally bifurcates at the level of G(i), leading to different effects depending on the Galpha isoform.