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TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells.

Quick K, Zhao J, Eijkelkamp N, Linley JE, Rugiero F, Cox JJ, Raouf R, Gringhuis M, Sexton JE, Abramowitz J, Taylor R, Forge A, Ashmore J, Kirkwood N, Kros CJ, Richardson GP, Freichel M, Flockerzi V, Birnbaumer L, Wood JN - Open Biol (2012)

Bottom Line: Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents.Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation.FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.

ABSTRACT
Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents. Double TRPC3/TRPC6 knock-out mice also showed hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation. FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines. TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes.

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Selective hearing deficit in TRPC3/TRPC6 DKO mice. (a) Preyer reflex score of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups) to a click box device that emits a 90 dSB toneburst centred around 20 kHz frequency. (b) Reaching response, a measure of vestibular function, of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups). (c) Swim test ability, number of head submersions in 1 min (n = 6 in all groups). (d) Auditory brain-stem recording (ABR) response thresholds to tone bursts of WT (n = 8, black squares) and TRPC3/TRPC6 DKO mice (n = 9, red circles). Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, movies S1–S5 for exemplar videos of the click box and swim test.
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RSOB120068F6: Selective hearing deficit in TRPC3/TRPC6 DKO mice. (a) Preyer reflex score of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups) to a click box device that emits a 90 dSB toneburst centred around 20 kHz frequency. (b) Reaching response, a measure of vestibular function, of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups). (c) Swim test ability, number of head submersions in 1 min (n = 6 in all groups). (d) Auditory brain-stem recording (ABR) response thresholds to tone bursts of WT (n = 8, black squares) and TRPC3/TRPC6 DKO mice (n = 9, red circles). Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, movies S1–S5 for exemplar videos of the click box and swim test.

Mentions: Adult TRPC3/C6 DKO mice, but not single knock-outs appeared to have a hearing loss. We therefore examined the responses of the mouse lines to high-intensity sound. The TRPC3/TRPC6 DKO mice did not show a Preyer reflex response to loud tones centred around 20 kHz at 90 dB delivered by a custom-built click box, while single knock-out mice displayed normal responses (figure 6a and electronic supplementary material, movies S1–S4), indicating hearing deficits in DKOs only. Deafness syndromes are often associated with deficits in the vestibular system [5]. Trunk curl measurements and swim test behaviour showed that there was also a vestibular deficit in the DKO mice despite normal rotarod performance (see electronic supplementary material, figure S2), while there were no significant differences between WT and single knock-out animals (figure 6b,c). Analyses of other mutant mouse strains have shown that rotarod tests do not necessarily correlate with subtle vestibular deficits [28].Figure 6.


TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells.

Quick K, Zhao J, Eijkelkamp N, Linley JE, Rugiero F, Cox JJ, Raouf R, Gringhuis M, Sexton JE, Abramowitz J, Taylor R, Forge A, Ashmore J, Kirkwood N, Kros CJ, Richardson GP, Freichel M, Flockerzi V, Birnbaumer L, Wood JN - Open Biol (2012)

Selective hearing deficit in TRPC3/TRPC6 DKO mice. (a) Preyer reflex score of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups) to a click box device that emits a 90 dSB toneburst centred around 20 kHz frequency. (b) Reaching response, a measure of vestibular function, of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups). (c) Swim test ability, number of head submersions in 1 min (n = 6 in all groups). (d) Auditory brain-stem recording (ABR) response thresholds to tone bursts of WT (n = 8, black squares) and TRPC3/TRPC6 DKO mice (n = 9, red circles). Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, movies S1–S5 for exemplar videos of the click box and swim test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376737&req=5

RSOB120068F6: Selective hearing deficit in TRPC3/TRPC6 DKO mice. (a) Preyer reflex score of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups) to a click box device that emits a 90 dSB toneburst centred around 20 kHz frequency. (b) Reaching response, a measure of vestibular function, of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice (n = 6 in all groups). (c) Swim test ability, number of head submersions in 1 min (n = 6 in all groups). (d) Auditory brain-stem recording (ABR) response thresholds to tone bursts of WT (n = 8, black squares) and TRPC3/TRPC6 DKO mice (n = 9, red circles). Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, movies S1–S5 for exemplar videos of the click box and swim test.
Mentions: Adult TRPC3/C6 DKO mice, but not single knock-outs appeared to have a hearing loss. We therefore examined the responses of the mouse lines to high-intensity sound. The TRPC3/TRPC6 DKO mice did not show a Preyer reflex response to loud tones centred around 20 kHz at 90 dB delivered by a custom-built click box, while single knock-out mice displayed normal responses (figure 6a and electronic supplementary material, movies S1–S4), indicating hearing deficits in DKOs only. Deafness syndromes are often associated with deficits in the vestibular system [5]. Trunk curl measurements and swim test behaviour showed that there was also a vestibular deficit in the DKO mice despite normal rotarod performance (see electronic supplementary material, figure S2), while there were no significant differences between WT and single knock-out animals (figure 6b,c). Analyses of other mutant mouse strains have shown that rotarod tests do not necessarily correlate with subtle vestibular deficits [28].Figure 6.

Bottom Line: Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents.Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation.FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.

ABSTRACT
Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents. Double TRPC3/TRPC6 knock-out mice also showed hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation. FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines. TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes.

Show MeSH
Related in: MedlinePlus