L-type channel inactivation balances the increased peak calcium current due to absence of Rad in cardiomyocytes.
L-type channel inactivation balances the increased peak calcium current due to absence of Rad in cardiomyocytes.
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DOI：
10.1085/jgp.202012854
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发表时间：
2021-09-06
期刊：
影响因子：
--
通讯作者：
Satin J
中科院分区：
文献类型：
--
作者：
Ahern BM;Sebastian A;Levitan BM;Goh J;Andres DA;Satin J
Ahern et al.表明Rad的缺乏不依赖于β-肾上腺素能受体信号而增加L型钙离子内流的峰值。这一增加的峰值电流由通道失活实现动态平衡，允许在不延长动作电位的情况下增强收缩。Rad的丧失是安全正性肌力支持的潜在治疗靶点。L钙通道(LTCC)提供触发钙离子，以分级方式启动心肌收缩，并受L钙电流(ICa，L)的幅度和动力学调节。LTCC的失活受到控制以微调钙流，并由电压依赖失活(VDI)和钙依赖失活(CDI)控制。Rad是一种单体G蛋白，调节ICa，L，最近被证明在β-肾上腺素能受体(β-AR)对ICa，L的调节中起关键作用。我们以前的工作表明，心肌细胞特异性Rad基因敲除(CRadKo)导致收缩功能增强，其基础是ICa峰值升高，L，但没有病理重构。在这里，我们试图测试Rad耗竭的LTCC是否独立于β-AR功能参与战斗或逃跑反应，导致ICA，L动态修改以动态平衡平衡心肌细胞功能。我们从诱导型cRadKO和对照组(CTRL)小鼠的心室肌细胞中记录了全细胞ICa，L。异丙肾上腺素刺激的CTRL心肌细胞ICa、L的动力学与未刺激的cRadKO心肌细胞无明显差别。CRadKO心肌细胞CDI和VDI均增强，动作电位时程和QT间期无差异。为了证实Rad丢失独立于β-AR刺激调节LTCC，我们将β1，β2-AR双基因敲除小鼠与cRadKO杂交，得到了Rad诱导的三重基因敲除小鼠。在不表达β1、β2-AR的心肌细胞中缺失Rad仍可产生调节的ICA、L和升高的基础心功能。因此，在缺乏Rad的情况下，钙离子内流的增加是由加速的CDI和VDI平衡的。我们的结果表明，Rad的缺失可以在没有β1，β2-AR信号参与的情况下对LTCC进行调制，并且Rad的缺失取代了β-AR信号对LTCC的作用，从而增强了在体心功能。
Ahern et al. show that the absence of Rad increases peak L-type calcium influx independently of β-adrenergic receptor signaling. This increased peak current is homeostatically balanced by channel inactivation, allowing enhanced contraction without action potential prolongation. The loss of Rad is a potential therapeutic target for safe positive inotropic support. The L-type Ca2+ channel (LTCC) provides trigger calcium to initiate cardiac contraction in a graded fashion that is regulated by L-type calcium current (ICa,L) amplitude and kinetics. Inactivation of LTCC is controlled to fine-tune calcium flux and is governed by voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). Rad is a monomeric G protein that regulates ICa,L and has recently been shown to be critical to β-adrenergic receptor (β-AR) modulation of ICa,L. Our previous work showed that cardiomyocyte-specific Rad knockout (cRadKO) resulted in elevated systolic function, underpinned by an increase in peak ICa,L, but without pathological remodeling. Here, we sought to test whether Rad-depleted LTCC contributes to the fight-or-flight response independently of β-AR function, resulting in ICa,L kinetic modifications to homeostatically balance cardiomyocyte function. We recorded whole-cell ICa,L from ventricular cardiomyocytes from inducible cRadKO and control (CTRL) mice. The kinetics of ICa,L stimulated with isoproterenol in CTRL cardiomyocytes were indistinguishable from those of unstimulated cRadKO cardiomyocytes. CDI and VDI are both enhanced in cRadKO cardiomyocytes without differences in action potential duration or QT interval. To confirm that Rad loss modulates LTCC independently of β-AR stimulation, we crossed a β1,β2-AR double-knockout mouse with cRadKO, resulting in a Rad-inducible triple-knockout mouse. Deletion of Rad in cardiomyocytes that do not express β1,β2-AR still yielded modulated ICa,L and elevated basal heart function. Thus, in the absence of Rad, increased Ca2+ influx is homeostatically balanced by accelerated CDI and VDI. Our results indicate that the absence of Rad can modulate the LTCC without contribution of β1,β2-AR signaling and that Rad deletion supersedes β-AR signaling to the LTCC to enhance in vivo heart function.
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DOI：
10.1073/pnas.262372999
发表时间：
2002-12-24
影响因子：
11.1
作者：
Alseikhan, BA;DeMaria, CD;Yue, DT
通讯作者：
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影响因子：
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发表时间：
2018-11-01
影响因子：
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影响因子：
5.5
作者：
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影响因子：
5.5
作者：
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