Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes
Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes
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DOI：
10.1161/circulationaha.107.754051
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发表时间：
2008-04-08
期刊：
影响因子：
37.8
通讯作者：
Bers, Donald M.
中科院分区：
文献类型：
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作者：
Despa, Sanda;Tucker, Amy L.;Bers, Donald M.
背景 - 心脏 Na/K-ATP 酶 (NKA) 调节细胞内 Na ([Na](i))，进而影响细胞内 Ca，从而通过 Na/Ca 交换影响收缩性。最近的证据表明，NKA 相关的小跨膜蛋白磷酸化蛋白 (PLM) 的磷酸化介导 β 肾上腺素诱导的 NKA 刺激。方法和结果 - 在此，我们测试了 β 肾上腺素激活过程中 PLM 磷酸化是否限制了小鼠心室肌细胞中 [Na](i)、Ca 瞬时振幅的上升并引发心律失常。在野生型 (WT) 小鼠的肌细胞中，2 Hz 场刺激下，[ Na](i) 从 11.1 +/- 1.8 mmol/ L 增加至 15.2 +/- 1.5 mmol/ L 的平台期。异丙肾上腺素诱导 [ Na](i) 减少至 12.0 +/- 1.2 mmol/ L。在 PLM 敲除 (PLM-KO) 小鼠中，其中 β-肾上腺素能刺激不会激活 NKA，[Na](i) 在 2 Hz 时也会增加（从 10.4 +/- 1.2 到 17.0 +/- 1.5 mmol/ L），但异丙肾上腺素不会改变。 PLM 介导的 WT 小鼠 [Na](i) 减少可以限制异丙肾上腺素诱导的正性肌力状态。事实上，WT 小鼠中异丙肾上腺素诱导的 Ca 瞬变幅度的增加明显较小（PLM-KO 小鼠中为 5.2 +/- 0.4 倍，而 PLM-KO 小鼠中为 7.1 +/- 0.5 倍）。肌浆网 Ca 含量也是如此，WT 小鼠中肌浆网 Ca 含量增加了 1.27 +/- 0.09 倍，而 PLM-KO 小鼠中则增加了 1.53 +/- 0.09 倍。与 WT 小鼠相比，PLM-KO 小鼠的肌浆网 Ca 含量较高，与 PLM-KO 小鼠自发 Ca 瞬变和收缩的倾向增加有关。结论 - 这些数据表明 PLM 磷酸化和 NKA 刺激是交感神经战斗或逃跑反应的一个组成部分，缓和 [Na](i) 和细胞 Ca 负荷的上升，并可能限制 Ca 超载引起的心律失常。
Background - Cardiac Na/K-ATPase ( NKA) regulates intracellular Na ([Na](i)), which in turn affects intracellular Ca and thus contractility via Na/Ca exchange. Recent evidence shows that phosphorylation of the NKA-associated small transmembrane protein phospholemman ( PLM) mediates beta-adrenergic - induced NKA stimulation.Methods and Results - Here, we tested whether PLM phosphorylation during beta-adrenergic activation limits the rise in [ Na](i), Ca transient amplitude, and triggered arrhythmias in mouse ventricular myocytes. In myocytes from wild-type (WT) mice, [ Na](i) increased on field stimulation at 2 Hz from 11.1 +/- 1.8 mmol/ L to a plateau of 15.2 +/- 1.5 mmol/ L. Isoproterenol induced a decrease in [ Na](i) to 12.0 +/- 1.2 mmol/ L. In PLM knockout ( PLM-KO) mice in which beta-adrenergic stimulation does not activate NKA, [ Na](i) also increased at 2 Hz ( from 10.4 +/- 1.2 to 17.0 +/- 1.5 mmol/ L) but was unaltered by isoproterenol. The PLM-mediated decrease in [ Na](i) in WT mice could limit the isoproterenol-induced inotropic state. Indeed, the isoproterenol-induced increase in the amplitude of Ca transients was significantly smaller in the WT mice ( 5.2 +/- 0.4- versus 7.1 +/- 0.5- fold in PLM-KO mice). This also was the case for the sarcoplasmic reticulum Ca content, which increased by 1.27 +/- 0.09- fold in WT mice versus 1.53 +/- 0.09- fold in PLM-KO mice. The higher sarcoplasmic reticulum Ca content in PLM-KO versus WT mice was associated with an increased propensity for spontaneous Ca transients and contractions in PLM-KO mice.Conclusions - These data suggest that PLM phosphorylation and NKA stimulation are an integral part of the sympathetic fight-or-flight response, tempering the rise in [Na](i) and cellular Ca loading and perhaps limiting Ca overload - induced arrhythmias.