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- W1991363935 abstract "The human ether a-go-go-related gene (hERG) encodes rapidly activating delayed rectifier K+ current (IKr) in heart. Missense mutations in hERG lead to loss in IKr in patients with type 2 long QT (LQT2) syndrome. In native adult rat ventricular myocytes (ARVMs), which intrinsically lack IKr, we studied hERG current (IhERG) by expressing WT or T421M mutation-hERG protein using an adenoviral infection system. The T421M mutation was identified in the S1 transmembrane region of hERG in a 32-yr-old woman with LQT2. Isolated ARVMs were infected with WT or T421M-expressing adenovirus and IhERG was recorded from infected myocytes 4 days after infection. Expression of WT or T421M-hERG in ARVMs produced IhERG with peak tail current (prepulse to 50 mV, tail current recorded at -50 mV) of 9.9 ± 1.7 and 1.6 ± 0.1 pA/pF (mean ± SEM) respectively. Western blot analysis shows that T421M-hERG protein traffics similar to WT-hERG indicated by the presence of 135 and 155 kDa protein. The voltage dependence of activation for the T421M-hERG showed a marked positive shift of 38 mV (V1/2, 24.5 ± 2.3 mV) compared to WT (-13.5 ± 3.0 mV, p<0.05). The deactivation time constants were derived by fitting tail current decay as a double exponential at hyperpolarizing potentials and were 5-10 fold faster for T421M than WT-hERG. We conclude that in native ventricular myocytes, T421M channels traffic normally and undergo minimal voltage-dependent activation during cardiac action potential repolarization, which is a novel mechanism for loss of IKr. Our results emphasize the importance of S1 region in modulating gating properties of hERG channels. Our adenoviral-mediated, over- expression ARVM model may be exploited to study the changes in cardiac action potential waveforms in cardiomyocyte's native background." @default.
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- W1991363935 date "2009-02-01" @default.
- W1991363935 modified "2023-09-27" @default.
- W1991363935 title "Mechanism Of IKr Loss In Mutant T421M-hERG Expressing Rat Ventricular Myocytes" @default.
- W1991363935 doi "https://doi.org/10.1016/j.bpj.2008.12.893" @default.
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