کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2925038 1175926 2009 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Aminoglycoside antibiotics restore functional expression of truncated HERG channels produced by nonsense mutations
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی کاردیولوژی و پزشکی قلب و عروق
پیش نمایش صفحه اول مقاله
Aminoglycoside antibiotics restore functional expression of truncated HERG channels produced by nonsense mutations
چکیده انگلیسی

BackgroundPharmacologic restoration of the trafficking defects of HERG missense mutations has been documented. However, whether correction of HERG nonsense mutations is possible is unknown.ObjectiveThe purpose of this study was to investigate the effect of aminoglycoside antibiotics on the expression of nonsense mutants expected to produce truncated HERG channels.MethodsHERG channel and mutant currents were recorded by whole-cell patch clamp techniques. Pharmacologic rescue was applied by culturing the cells in 400 μg/mL G-418 or gentamicin for 24 hours.ResultsCurrent densities were significantly reduced in cells expressing R1014X and W927X mutants compared to those of cells expressing wild-type (WT) HERG. R863X and E698X mutants failed to generate any typical HERG currents. Mean peak tail current density of R1014X mutant was significantly lower than that of WT (3.9 ± 1.4 pA/pF, n = 8, vs 47.8 ± 6.3 pA/pF, n = 12, P <.05) and increased to 12.7 ± 3.3 pA/pF (n = 7, P <.05) and 18.3 ± 3.7 pA/pF (n = 8, P <.05) after G-418 and gentamicin treatment. The voltage dependence of activation of R1014X was also restored after drug treatment. Furthermore, expression of full-length proteins for R1014X induced by drugs was detected by western blot and confocal imaging. Similar results were observed in W927X. For R863X and E698X, however, gentamicin treatment had no effect. In the cells cotransfected with WT/R1014X, gentamicin and G-418 demonstrated different results: gentamicin, but not G-418, increased the current density by 2.2-fold (n = 12, P <.05).ConclusionThe study findings provide proof of principle that interventions designed to read through premature stop mutations may at least partially reverse the LQT2 phenotype in vitro.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Heart Rhythm - Volume 6, Issue 4, April 2009, Pages 553–560
نویسندگان
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