ZJU scientists discover mechanism of deafness genes TMCs

2018-01-31

Mutations in transmembrane channel like (TMC) proteins TMC1 and TMC2 cause deafness and vestibular defects in mammals. However, their precise action modes are elusive. On January 25, Professor KANG Lijun's group published a research article entitled “TMC Proteins Modulate Egg Laying and Membrane Excitability through a Background Leak Conductance in C. elegans” in the top-tier research journal Neuron. They revealed a novel role of TMC proteins in regulating of resting membrane potential and cellular excitability.

Membrane excitability is a unique feature for all excitable membranes that allows animals to quickly respond to various externaland internal stimuli.To maintain normal membrane excitability, various depolarizing background leak conductances must counteract with K+-leak conductances in both neurons and muscle cells. However, compared to the extensively characterized background K+-leak channels, relatively little is known about the molecular nature of depolarizing background leak conductances except the only one background Na+-leak channel family NCA/NALCN. However, NCA/NALCN channels are mainly expressed in neurons and extra Na+-leak conductances are still present in the absence of NCA/NALCN proteins. Therefore, unidentified membrane proteins must underlie the muscular depolarizing background leak conductances as well as the NCA/NALCN-independent neuronal leak conductances.

Transmembrane channel-like (TMC) proteins are a novel family of channel-like proteins conserved from C. elegans to humans. Eight TMC proteins are expressed in vertebrates, among which TMC1 and TMC2 are essential for mechanosensation in the auditory and vestibular hair cells. Although mutations in TMC1 and TMC2 cause deafness and vestibular defects, the precise functions and action modes of these two TMC proteins are still elusive. In addition, three other TMC proteins (TMC3, TMC4, and TMC7) are expressed in hair cells but their functions in hearing are largely unknown. The Drosophila genome encodes a single tmc homolog that acts in proprioception and food texture detection. In C. elegans, two tmc genes (tmc-1 and tmc-2) have been cloned, among which tmc-1 is required for the ASH nociceptive neuron-mediated alkaline, while the expression and function of tmc-2 remain uncharacterized.

In this study, Yue et al., found that the C. elegans TMC-1 is expressed in both neurons and muscle cells, while TMC-2 is exclusively expressed in muscle cells. Combining behavioral analysis, functional Ca2+ imaging, and patch-clamp recordings, they revealed that the disruption of TMC proteins hyperpolarizes membrane potential and reduces the rhythmic calcium activities of neurons and muscles involved in egg laying, thereby suppressing the C. elegans egg-laying behavior. Importantly, this egg-laying defect can be rescued by transgenic expression of TMC-1 and TMC-2 as well as mammalian TMC homologs. Furthermore, they revealed that TMC-1 and TMC-2 modulate neuronal and muscular excitability through a depolarizing background leak conductance. Taken together, this study demonstrate a novel role of TMC proteins in setting membrane potential and excitability in both neurons and muscle cells. Moreover, their studies establish TMC proteins as key components of muscular background leak conductances.

Using C. elegans model system, Yue et al. have revealed a novel role of TMC proteins in egg laying and membrane excitability. Since TMC proteins are evolutionarily conserved from C. elegans to humans, and the defect caused by loss of worm TMCs can be rescued by transgenic expression mammalian TMC homologs, their results may provide novel insights into the functions of mammalian TMC proteins.

This work was carried out by graduate students YUE Xiaomin, ZHAO Jian, LI Xiao et al., under the supervision of Professor KANG, in collaboration with Professor XIAO Rui at the University of Florida. The study was completed at the Center for Neuroscience, School of Medicine, Zhejiang University.

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KANG Lijun

Professor

Center for Neuroscience