Method for screening hERG potassium ion channel agonist and detecting toxicity

Abstract

The invention relates to a method for screening hERG potassium ion channel agonist and detecting toxicity. Particularly, the invention firstly relates to a fusion protein, which contains a fragment (which is used as the N end of the fusion protein, is from a position between 1st to 85th amino acid residues of the N end of the nemathelminth ERG family potassium ion channels UNC-103 protein and has the length of 75 to 85 amino acid residues), hERG or a fragment at least containing S1-S6 transmembrane domains and cyclic nucleotide binding domains, and a fragment (which is used as the C end of the fusion protein, is from a position between 590th to 829th of amino acid residues of the C end of the UNC-103 protein and has the length of 220 to 240 amino acid residues). The invention also relates to a polynucleotide sequence coding the fusion protein, a relevant transgenic nemathelminth, a relevant screening method and application. The inventor builds an in-vivo hERG-intracellular-transport-influence-recognizable compound molecule screening method for screening hERG inhibitors or LQTS (long QT syndrome) relevant channel mutant functional correcting agents for the first time; the novel path and method are provided for hERG toxicity detection and LQTS treatment medicine screening.

Description

technical field [0001] The invention relates to a method for screening hERG potassium ion channel agonists and detecting toxicity. Background technique [0002] Long QT syndrome (long QT syndrome, LQTS) is a kind of arrhythmia disease caused by abnormal myocardial ion channels, manifested as prolonged myocardial repolarization, reflected in the electrocardiogram as QT interval prolongation. LQTS can easily induce torsades de pointes (TdP), which can lead to palpitations, syncope, and even sudden death. LQTS can be divided into two types: congenital and acquired. Congenital LQTS is caused by gene mutations, mainly in KCNQ1, KCNH2 (encoding hERG potassium ion channel) and SCN5A plasma channel genes. Mutations in the hERG channel gene lead to type II LQTS (LQTS2), accounting for about 45% of the total LQTS incidence. Acquired LQTS mainly refers to the reversible prolongation of QT interval caused by drugs. Studies have shown that most drugs induce LQTS by inhibiting hERG pot...

AI Technical Summary

Problems solved by technology

However, these monitoring instruments are relatively expensive, and generally they can only detect transient hERG channel blockers or agonists that act on the cell membrane, and it is difficult to screen for those compounds that have a longer duration of action and regulate the intracellular transport of hERG channels

More importantly, there is no relevant screening system for corrective compounds that promote the re-membrane of trafficking-deficient mutant hERG channels

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