TMC2 Membrane Protein Introduction

Introduction of TMC2

Transmembrane channel-like protein 2 (TMC2) is a transmembrane protein consisting of 906 amino acids and is encoded by the TMC2 gene on chromosome 20. TMC2 gene in human belongs to the TMC gene family that includes eight paralogs (TMC1 to TMC8) in mammals. The eight TMC genes are divided into three subfamilies according to their sequence and genomic structure. TMC1, TMC2 and TMC3 belong to subfamily A and are expressed at low levels, while TMC4 to TMC8 are expressed at higher levels in various tissues. TMC2 shows the highest sequence similarity and phylogenetic relationship with TMC1 in TMC family members. TMC2 and TMC2 mRNA expression are detected in human fetal cochlea and mouse inner ear, respectively. TMC2 has an mRNA expression pattern associated with the onset of mechanical transduction and is localized to the tip of the intermediate and lower cilia.

The Function of TMC2 Membrane Protein

The ability of cochlear hair cells to convert sound to receptor potential depends on the presence of mechanoelectrical transducer (MET) channels in the stereocilia bundle. Sensory transduction in auditory and vestibular hair cells requires expression of TMC1 and TMC2 gene. TMC1 expression is persistent in cochlear and vestibular hair cells, whereas TMC2 expression is transient in cochlear hair cells but persistent in vestibular hair cells. As with TMC1, TMC2 is a component of the MET channel in hair cells of the mammalian inner ear and contributes to the pore-forming subunit of the neonatal channel. Mutations in the TMC1 gene cause loss of hearing, but when the exon encoding the first transmembrane domain of TMC2 is replaced by the lacZ reporter gene, the mice appear to be phenotypically normal: they had neither hearing loss nor significant abnormal vestibular behavior. In conclusion, TMC2 mutations have never been reported in human hearing loss or vestibular dysfunction. Although TMC2 is present during the initial assembly of the MET channel in early postnatal cochlear hair cells, it may be an evolutionary remnant that is not required for the highly specialized hair cells of the mature mammalian cochlea.

Fig.1 Schematic model of TMC1 and TMC2 functions. (a) TMC1 and TMC2 can serve as pore-forming subunits of mechanical transduction channels. (b) TMCI and TMC2 act as essential linker proteins that convey tension from the tip link to the transduction channel. (c) TMC1 and TMC2 can be used to anchor the transduction channel to the cytoskeleton. (Kawashima, 2015)

Application of TMC2 Membrane Protein in Literature

1. Corns L.F., et al. TMC2 Modifies Permeation Properties of the Mechanoelectrical Transducer Channel in Early Postnatal Mouse Cochlear Outer Hair Cells. Frontiers in Molecular Neuroscience. 2017, 10:326. PubMed ID: 29093662
   
   

   This article points out that TMC2 expression in immature cochlea may be an evolutionary remnant although it is required for mechanical transduction in mature vestibular hair cells.

2. Giese A.P.J., et al. CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nature Communications. 2017, 8(1):43. PubMed ID: 28663585
   
   

   This article reports that the interaction of calcium and integrin binding protein (CIB2) with TMC1 and TMC2 is critical for the mechanical transduction of auditory hair cells.

3. Kurima K., et al. TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia. Cell Reports. 2015, 12(10):1606-17. PubMed ID: 26321635
   
   

   This study verifies that TMC1 and TMC2 are components of a stereocilia mechanoelectrical transduction channel complex.

4. Pan B., et al. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron. 2013, 79(3):504-15. PubMed ID: 23871232
   
   

   This article demonstrates that TMC1 and TMC2 are components of the hair cell transduction pathway and contribute to the osmotic properties.

5. Terra R., et al. To Investigate the Necessity of TMC2 Upregulation in T Cells during T Cell Immune Responses. Plos One. 2013, 8(12):e82808. PubMed ID: 24391722
   
   

   This study confirms that TMC1 gene mutations, rather than TMC2 mutations, are a common cause of autosomal recessive hereditary non-syndromic hearing impairment.

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Reference

1. Kawashima Y, et al. (2015). Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation. Pflügers Archiv-European Journal of Physiology. 467(1):85-94.

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