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Scientists establish a new method of ion channel drug research

2018-09-30
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On September 26, the journal Nature Communications published an online publication of the Cai Shiqing Research Group of the Institute of Neuroscience of the Chinese Academy of Sciences, the Center for Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences, the State Key Laboratory of Neuroscience and the Beijing Anzhen Hospital of Capital Medical University Professor Lan Feng’s team collaborated on a research paper titled “Using ion channel disease nematode models to screen small molecule compounds that regulate ion channel function”. This study established a method for high-throughput screening of compounds that target ion channels in small animal systems, and found some compounds that can restore the function of disease-causing ion channel mutants, and clarified their mechanism of action to provide treatment for ion channel diseases.

Ion channel

Ion channels provide pathways for specific ions to enter and exit cells. They are an important part of the molecular basis of biological electrical activity. Ion channels are essentially gateways in cell membranes that selectively allow the passage of particular ions, and that are induced to open or close by a variety of mechanisms. Two important types are ligand-gated channels and voltagegated channels.

Ion channels are involved in regulating the electrical signal conduction of the nervous system and play a key role in important physiological processes such as heart beat. There are currently more than 60 ion channels related to human diseases or dysfunctions (such as epilepsy and arrhythmia). Hereditary gene mutations mainly cause ion channel function abnormalities through four mechanisms:

1. Change the process of gene transcription and translation;

2. Cause abnormal folding and assembly of ion channel proteins, and membrane transport defects;

3. Change the gate control and power of ion channels Academic characteristics;

4. Change the ion selectivity of ion channels, etc.

Therefore, restoring the functions of pathogenic mutants of different ion channels requires different strategies to achieve precise treatment of ion channel diseases. Current ion channel compound screening methods mainly focus on compounds that regulate the gating and kinetic properties of ion channels (such as blockers and activators), while there are few studies on compounds that regulate ion channel Biogenesis. However, more and more studies have shown that gene mutations that cause abnormal folding of ion channels, which in turn lead to protein retention in the endoplasmic reticulum, is an important pathogenic mechanism of ion channel diseases. Therefore, there is an urgent need to establish a method for high-throughput screening of compounds that regulate ion channel functions from different levels (electrophysiological properties and biological processes, etc.) under physiological conditions.

Ion channels and electrical excitability

Excitable ceils generate an all-or-nothing action potential in response to membrane depolarisation. This occurs in most neurons and muscle cells, and in some gland ceils. The ionic basis and time course of the response varies between tissues.

The regenerative response results from the depolarising current associated with opening of voltage-gated cation channels (mainly Na+ and Ca2+,). It is terminated by inactivation of these channels accompanied by opening of K+ channels.

These voltage-gated channels exist in many molecular varieties, with specific functions in different types of cell.

The membrane of the 'resting' cell is relatively permeable to K+ but impermeable to Na+  and Ca2+ Drugs or mediators that open K+ channels reduce membrane excitability, as do inhibitors of Na+ or Ca2+ channel function. Blocking K+ channels or activating Na+ or Ca2+ channels increases excitability.

Cardiac muscle cells, some neurons and some smooth muscle cells generate spontaneous action potentials whose amplitude, rate and rhythm are affected by drugs that affect ion channel function.

The hERG potassium channel mainly mediates the repolarization process of the action potential of cardiomyocytes, and its abnormal function can lead to long QT syndrome (a kind of arrhythmia disease) and even sudden death. The UNC-103 potassium channel of model animal Caenorhabditis elegans (nematode for short) is highly homologous to human-derived ERG, which controls important behaviors such as nematode movement and egg laying. In this study, the researchers expressed the human source picture of the hERG potassium channel in C. elegans. The enhancement of potassium channel function will significantly change the excitability of the worm’s neurons and muscle cells, causing the worm to produce obvious behavioral defects (such as egg laying and locomotion). ); And changes in the function of the hERG potassium ion channel will lead to changes in nematode behavior, which provides convenient conditions for ion channel compound screening. The researchers screened about 14,800 small molecule compounds by observing the behavior of nematodes, combined with the corresponding fluorescent protein markers, and successfully found the compound ALA that inhibits the transport of the hERG channel membrane and the compound that restores the function of the transport-defective hERGA561V channel. IDB. Picture Prostratin and IDB promote the membrane transport of hERGA561V channel mutants, improve channel function, and can correct electrophysiological abnormalities in the cardiomyocyte model of human induced pluripotent stem cells (hiPSC) differentiated into long QT syndrome. Further studies have shown that Prostratin and IDB can increase the function of hERGA561V by activating PKCε signal and then phosphorylating the S606 site located in the pore region of the hERG channel.

The method for screening nematode ion channel compounds established in this study has the advantages of simple construction, simple operation, high throughput and low cost. Combined with the high-throughput analysis platform for nematode behavior that the research group has developed, this compound screening method based on nematode ion channel disease models is expected to play an important role in the development of ion channel drugs.

The research work was mainly completed by doctoral students Jiang Qiang and Li Kai under the guidance of Cai Shiqing and Lan Feng. Lu Wenjing of Beijing Anzhen Hospital and Li Shuang of Ding Qiurong’s research group of Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences participated in the research. This work was supported by the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, the National Natural Science Foundation of China and the National Natural Science Foundation of China.

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