Biophysical defects of an SCN5A V1667I mutation associated with epinephrine-induced marked QT prolongation
Biophysical defects of an SCN5A V1667I mutation associated with epinephrine-induced marked QT prolongation
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DOI：
10.1111/jce.14575
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发表时间：
2020-06-02
影响因子：
2.7
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
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作者：
Nakajima, Tadashi;Dharmawan, Tommy;Kurabayashi, Masahiko
背景肾上腺素输注试验（EIT）通常在LQT 1中诱导显著的QT延长，但在LQT 3中不诱导，而β受体阻滞剂治疗的疗效在LQT 1中确定，但在LQT 3中不确定。我们遇到了一个LQT 3家族，与SCN 5A V1667 I突变，表现出肾上腺素诱导的显着QT delayation.Methods野生型（WT）或V1667 I-SCN 5A瞬时表达到tsA-201细胞，和全细胞钠电流（I-Na）记录使用膜片钳技术。为了模拟肾上腺素的作用，在应用蛋白激酶A（PKA）激活剂8-CPT-cAMP后记录I-Na结果V1667 I-I-Na的峰密度明显大于WT-I-Na（WT：469 +/-48pA/pF，n = 20; V1667I：690 +/-62pA/pF，n = 19，P < .01）。V1667 I-I-Na的稳态活化（SSA）和快速失活率与WT-I-Na相当。与WT-I-Na相比，V1667 I-I-Na在稳态失活（SSI）中显示出显著的去极化偏移（V-1/2-WT：-88.1 +/- 0.8 mV，n = 17; V1667 I：-82.5 +/- 1.1 mV，n = 17，P <0.01），这增加了窗电流。河豚毒素（30 μ M）敏感的持久性V1667 I-I-Na与WT-I-Na相当。然而，与WT-1-Na相比，斜坡脉冲方案（RPP）显示V1667 I-I-Na的驼峰增加。尽管8-CPT-cAMP使WT-I-Na和V1667 I-I-Na中SSA向超极化电位的偏移程度相同，但其使V1667 I-I-Na中SSI向超极化电位的偏移程度远小于WT-I-Na（V-1/2-WT：-92.7 +/- 1.3 mV，n = 6; V1667 I：-85.3 +/- 1.6 mV，n = 6，P < .01）。一致地，RPP显示增加驼峰V1667 I-I-Na，但不是在WT-I-Na.Conclusions我们证明了增加V1667 I-I-Na PKA激活，这可能提供了一个合理的β受体阻滞剂治疗的疗效在某些情况下LQT 3。
Background The epinephrine infusion test (EIT) typically induces marked QT prolongation in LQT1, but not LQT3, while the efficacy of beta-blocker therapy is established in LQT1, but not LQT3. We encountered an LQT3 family, with an SCN5A V1667I mutation, that exhibited epinephrine-induced marked QT prolongation.Methods Wild-type (WT) or V1667I-SCN5A was transiently expressed into tsA-201 cells, and whole-cell sodium currents (I-Na) were recorded using patch-clamp techniques. To mimic the effects of epinephrine, I-Na was recorded after the application of protein kinase A (PKA) activator, 8-CPT-cAMP (200 mu M), for 10 minutes.Results The peak density of V1667I-I-Na was significantly larger than WT-I-Na (WT: 469 +/- 48 pA/pF, n = 20; V1667I: 690 +/- 62 pA/pF, n = 19, P < .01). The steady-state activation (SSA) and fast inactivation rate of V1667I-I-Na were comparable to WT-I-Na. V1667I-I-Na displayed a significant depolarizing shift in steady-state inactivation (SSI) in comparison to WT-I-Na (V-1/2-WT: -88.1 +/- 0.8 mV, n = 17; V1667I: -82.5 +/- 1.1 mV, n = 17, P < .01), which increases window currents. Tetrodotoxin (30 mu M)-sensitive persistent V1667I-I-Na was comparable to WT-I-Na. However, the ramp pulse protocol (RPP) displayed an increased hump in V1667I-I-Na in comparison to WT-I-Na. Although 8-CPT-cAMP shifted SSA to hyperpolarizing potentials in WT-I-Na and V1667I-I-Na to the same extent, it shifted SSI to hyperpolarizing potentials much less in V1667I-I-Na than in WT-I-Na (V-1/2-WT: -92.7 +/- 1.3 mV, n = 6; V1667I: -85.3 +/- 1.6 mV, n = 6, P < .01). Concordantly, the RPP displayed an increased hump in V1667I-I-Na, but not in WT-I-Na.Conclusions We demonstrated an increase of V1667I-I-Na by PKA activation, which may provide a rationale for the efficacy of beta-blocker therapy in some cases of LQT3.