Hold live cell excitability! A new breakthrough in the mechanism of the gene

Guide

Mutations in the Tmc1 and Tmc2 genes have led to a family of hereditary deafness and have received much attention. On January 25th, Kang Lijun's research group of Zhejiang University School of Medicine published the latest research paper in Neuron magazine, revealing that TMC-1 and TMC-2 can maintain the resting membrane potential of nerve and muscle cells through a constant background Na+ current. Excitability and regulation of the corresponding behavioral paradigm.

It is well known that the realization of normal life activities of living organisms depends on the tissues and cells of the body. Every living cell has a certain excitement. As long as it is alive, it is a "squeaky"! As for the energetic "turning over", it is still a "snap" that depends on the cell membrane. The degree of synergy and cooperation of the various ion channels.

Resting membrane potential is an important indicator to measure the degree of excitability of a cell, while background Na+ leakage current and background K+ leakage current play an important regulatory role. Currently, the NALCN protein family is the only known family of background Na+ channel proteins. Its mutation causes the respiratory rhythm of the newborn mice to be lost, and eventually the poor mice will die of brain due to suffocation. It can be seen that without the background Na+ channel, even normal breathing is difficult to maintain, which is a terrible thing!

Another, more tragic fact, there are 2 to 3 deaf children in every 1,000 newborns in China, and more than half of them are hereditary deafness caused by a mutation in the cariogenic gene. Transmembrane channel-like proteins (TMC) are a new class of ion channel-like proteins. TMC1 is a component necessary for the detection of sonic stimulation in the inner ear, and the TMC1 gene mutation directly leads to congenital deafness. The paper published in the latest Nature magazine shows that the mutation of the Tmc1 gene can be corrected by the CRISPR-Cas9 gene editing technology to restore the hearing of mutant mice. It has also been reported in the literature that TMC1 is a mechanically sensitive ion channel that is sensitive to acoustic wave stimulation by hair cells. However, this hypothesis lacks experimental confirmation that the physiological functions and mechanisms of other proteins in the TMC family have long been known.

The Kanglijun team of Zhejiang University, using C. elegans as a model, found that mutations in the tmc-1 and tmc-2 genes caused nematode spawning defects, and a large number of eggs could not be discharged until the mother's stomach was broken. In the exploration of the mechanism of action, it was found that TMC-1 and TMC-2 proteins can maintain related neurons and muscle cells by mediating background Na+ current (similar to the NALCN protein family) (NALCN/NCA is not expressed in muscle, TMC) At present, the resting membrane potential and excitability of the head in the muscles, in order to regulate the oviposition behavior of the nematode. The fact of bloody forest, because of the loss of TMC protein function, human and mouse deafness is deaf, and nematodes are more tragic to dystocia.

Some people may ask, in the insects, the TMC protein mediates the background Na+ current affecting cell excitability, but does the homologous protein in mammals also work like this? So, the Kanglijun research group will be human and mouse. The normal TMC protein expression in the tmc gene mutant nematode was found to not only restore the defective phenotype of dysfunctional nematodes, but also restore rhythmic calcium oscillations and electrophysiological membrane potentials as well as background Na+ currents in related neurons and muscle cells. Therefore, TMC proteins are highly evolutionarily conserved in their mechanism of action. Maybe it’s not “inaudible”, but the inner ear hair cells are not excited enough to “willing to hear”, just as the worm is not “not able to live”, but its tissue cells are weak to “live”! Interestingly, the three rings The antidepressant imiprimine inhibition or gene knockout of the background K+ ion channel on muscle cells can rescue behavioral defects that restore the tmc gene mutant. Therefore, the genetic defects associated with the tmc gene may be rescued by chemical drug regulation or by editing the relevant action proteins (such as the K channel). This study not only proposed the possibility of a second type of background sodium channel family, but also laid a scientific foundation for the early diagnosis, treatment and drug development of hereditary deafness and related neuromuscular diseases.

It is reported that Ph.D. students in neurobiology of Zhejiang University, Yue Xiaomin, Zhao Jian, and master student Li Xiao are the first authors of the thesis. Dr. Kang Lijun, a researcher at the Institute of Neuroscience at Zhejiang University, and Dr. Xiao Rui from the Institute of Aging at the University of Florida, are co-authors of this paper.

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