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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 deficits in innocuous mechanosensation in TRPC3/TRPC6 double knock-out (DKO) mice. (a) Fifty per cent threshold to mechanical stimulation using von Frey hairs in wild-type (WT) (n = 8), TRPC3/TRPC6 DKO (n = 9), TRPC3 knock-out (KO) (n = 7) and TRPC6 KO (n = 10) mice. (b) Responses of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice to a cotton bud applied to the plantar surface of the hind paw (n = 6/group). (c) Response to noxious mechanical stimulation using a Randall–Selitto apparatus in WT (n = 7), TRPC3/TRPC6 DKO (n = 9), TRPC3 KO (n = 6) and TRPC6 KO (n = 7) mice. (d) Response to noxious thermal stimulation using Hargreaves’ apparatus in TRPC3/TRPC6 DKO (n = 14), TRPC3 KO (n = 11), TRPC6 KO (n = 15) and WT (n = 12) mice. Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, figure S2.
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RSOB120068F2: Selective deficits in innocuous mechanosensation in TRPC3/TRPC6 double knock-out (DKO) mice. (a) Fifty per cent threshold to mechanical stimulation using von Frey hairs in wild-type (WT) (n = 8), TRPC3/TRPC6 DKO (n = 9), TRPC3 knock-out (KO) (n = 7) and TRPC6 KO (n = 10) mice. (b) Responses of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice to a cotton bud applied to the plantar surface of the hind paw (n = 6/group). (c) Response to noxious mechanical stimulation using a Randall–Selitto apparatus in WT (n = 7), TRPC3/TRPC6 DKO (n = 9), TRPC3 KO (n = 6) and TRPC6 KO (n = 7) mice. (d) Response to noxious thermal stimulation using Hargreaves’ apparatus in TRPC3/TRPC6 DKO (n = 14), TRPC3 KO (n = 11), TRPC6 KO (n = 15) and WT (n = 12) mice. Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, figure S2.

Mentions: We examined global TRPC3 and TRPC6 knock-out mice, as well as DKO mice in a range of behavioural assays [22]. Motor co-ordination on a rotarod was normal in all mouse lines (see electronic supplementary material, figure S2), allowing us to test responses to mechanical and thermal stimuli. Withdrawal responses to von Frey hairs or detection of a cotton bud (a recent assay described in Garrison et al. [20]) were blunted in double but not single knock-out mice, indicating a deficit in mechanosensation (figure 2a,b). However, threshold responses to noxious mechanical pressure applied with a Randall–Selitto apparatus (figure 2c), as well as threshold responses to noxious heat applied with a Hargreaves apparatus (figure 2d) were normal in single and double TRPC3/TRPC6 knock-outs.Figure 2.


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 deficits in innocuous mechanosensation in TRPC3/TRPC6 double knock-out (DKO) mice. (a) Fifty per cent threshold to mechanical stimulation using von Frey hairs in wild-type (WT) (n = 8), TRPC3/TRPC6 DKO (n = 9), TRPC3 knock-out (KO) (n = 7) and TRPC6 KO (n = 10) mice. (b) Responses of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice to a cotton bud applied to the plantar surface of the hind paw (n = 6/group). (c) Response to noxious mechanical stimulation using a Randall–Selitto apparatus in WT (n = 7), TRPC3/TRPC6 DKO (n = 9), TRPC3 KO (n = 6) and TRPC6 KO (n = 7) mice. (d) Response to noxious thermal stimulation using Hargreaves’ apparatus in TRPC3/TRPC6 DKO (n = 14), TRPC3 KO (n = 11), TRPC6 KO (n = 15) and WT (n = 12) mice. Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, figure S2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSOB120068F2: Selective deficits in innocuous mechanosensation in TRPC3/TRPC6 double knock-out (DKO) mice. (a) Fifty per cent threshold to mechanical stimulation using von Frey hairs in wild-type (WT) (n = 8), TRPC3/TRPC6 DKO (n = 9), TRPC3 knock-out (KO) (n = 7) and TRPC6 KO (n = 10) mice. (b) Responses of WT, TRPC3/TRPC6 DKO, TRPC3 KO and TRPC6 KO mice to a cotton bud applied to the plantar surface of the hind paw (n = 6/group). (c) Response to noxious mechanical stimulation using a Randall–Selitto apparatus in WT (n = 7), TRPC3/TRPC6 DKO (n = 9), TRPC3 KO (n = 6) and TRPC6 KO (n = 7) mice. (d) Response to noxious thermal stimulation using Hargreaves’ apparatus in TRPC3/TRPC6 DKO (n = 14), TRPC3 KO (n = 11), TRPC6 KO (n = 15) and WT (n = 12) mice. Data are expressed as mean ± s.e.m. *p < 0.05; **p < 0.01; ***p < 0.001. See also electronic supplementary material, figure S2.
Mentions: We examined global TRPC3 and TRPC6 knock-out mice, as well as DKO mice in a range of behavioural assays [22]. Motor co-ordination on a rotarod was normal in all mouse lines (see electronic supplementary material, figure S2), allowing us to test responses to mechanical and thermal stimuli. Withdrawal responses to von Frey hairs or detection of a cotton bud (a recent assay described in Garrison et al. [20]) were blunted in double but not single knock-out mice, indicating a deficit in mechanosensation (figure 2a,b). However, threshold responses to noxious mechanical pressure applied with a Randall–Selitto apparatus (figure 2c), as well as threshold responses to noxious heat applied with a Hargreaves apparatus (figure 2d) were normal in single and double TRPC3/TRPC6 knock-outs.Figure 2.

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