Light Peter E, Wallace Catriona H R, Dyck Jason R B
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Circulation. 2003 Apr 22;107(15):1962-5. doi: 10.1161/01.CIR.0000069269.60167.02. Epub 2003 Apr 7.
Some PRKAG2 mutations in the human gene encoding for the gamma-subunit of the adenosine monophosphate-activated protein kinase (AMPK) recently have been shown to cause rhythm disturbances (often fatal) in affected patients.
Rat ventricular myocytes were infected with an adenoviral vector designed to express a truncated constitutively active mutant (T172D) of the AMPK alpha1-subunit (CA-AMPK). The human cardiac sodium channel hH1 and CA-AMPK were also coexpressed in a mammalian cell line. Patch-clamp techniques were used to measure myocyte action potentials and recombinant hH1 sodium channel currents. Our results demonstrate that action potential duration is significantly prolonged in myocytes expressing the CA-AMPK construct, leading to the production of potentially arrhythmogenic early afterdepolarizations. Recombinant sodium channel current analysis revealed that expression of CA-AMPK significantly slowed open-state inactivation and shifted the voltage-activation curve in a hyperpolarizing direction.
We propose that sodium channels may be substrates for AMPK, possibly contributing to the observed arrhythmogenic activity in patients with some PRKAG2 mutations.
最近研究表明，人类基因中编码单磷酸腺苷激活蛋白激酶（AMPK）γ亚基的某些PRKAG2突变会导致受影响患者出现节律紊乱（通常是致命的）。
用一种腺病毒载体感染大鼠心室肌细胞，该载体设计用于表达AMPKα1亚基的截短型组成型活性突变体（T172D）（CA-AMPK）。人类心脏钠通道hH1和CA-AMPK也在一种哺乳动物细胞系中共表达。采用膜片钳技术测量心肌细胞动作电位和重组hH1钠通道电流。我们的结果表明，在表达CA-AMPK构建体的心肌细胞中，动作电位持续时间显著延长，导致产生潜在致心律失常的早期后去极化。重组钠通道电流分析显示，CA-AMPK的表达显著减慢了开放状态失活，并使电压激活曲线向超极化方向移动。
我们提出钠通道可能是AMPK的作用底物，这可能是一些PRKAG2突变患者出现观察到的致心律失常活性的原因。
