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|Title:||TRPA1 contributes to specific mechanically activated currents and sensory neuron mechanical hypersensitivity|
Castro Kraftchenko, J.
|Citation:||Journal of Physiology-London, 2011; 589(14):3575-3593|
|Publisher:||Blackwell Publishing Ltd|
|Stuart M Brierley, Joel Castro, Andrea M Harrington, Patrick A Hughes, Amanda J Page, Grigori Y Rychkov and L. Ashley Blackshaw|
|Abstract:||The mechanosensory role of TRPA1 and its contribution to mechanical hypersensitivity in sensory neurons remains enigmatic. We elucidated this role by recording mechanically activated currents in conjunction with TRPA1 over-and under-expression and selective pharmacology. First, we established that TRPA1 transcript, protein and functional expression are more abundant in smaller-diameter neurons than larger-diameter neurons, allowing comparison of two different neuronal populations. Utilizing whole cell patch clamping, we applied calibrated displacements to neurites of DRG neurons in short-term culture and recorded mechanically activated currents termed Intermediately- (IAMC), Rapidly- (RAMC) or Slowly-Adapting (SAMC). TRPA1 deletion (-/-) significantly reduced maximum IAMC amplitude by 43% in small-diameter neurons compared with wild-type (+/+) neurons. All other mechanically activated currents in small- and large-diameter TRPA1-/- neurons were unaltered. 73% of TRPA1+/+ small-diameter neurons responding to the TRPA1 agonist AITC displayed IAMC to neurite displacement, which were significantly enhanced after AITC addition. The TRPA1 antagonist HC-030031 significantly decreased TRPA1+/+ IAMC amplitudes, but only in AITC responsive neurons. Using a transfection system we also showed TRPA1 over-expression in TRPA1+/+ small-diameter neurons increases IAMC amplitude, an effect reversed by HC-030031. Furthermore, TRPA1 introduction into TRPA1-/- small-diameter neurons restored IAMC amplitudes to TRPA1+/+ levels, which was subsequently reversed by HC-030031. In summary our data demonstrate TRPA1 makes a specific contribution to normal mechanosensation in a distinct subset of DRG neurons. Furthermore, they also provide new, direct evidence illustrating mechanisms by which sensitization or over-expression of TRPA1 enhances nociceptor mechanosensitivity. Overall, these findings suggest TRPA1 has the capacity to tune neuronal mechanosensitivity depending on its degree of activation or expression.|
|Keywords:||Ganglia, Spinal; Cells, Cultured; Animals; Mice, Inbred C57BL; Mice, Knockout; Mice; Hyperalgesia; Acetanilides; Isothiocyanates; Purines; Patch-Clamp Techniques; Mechanotransduction, Cellular; Action Potentials; Transient Receptor Potential Channels; Sensory Receptor Cells; TRPA1 Cation Channel|
|Rights:||Copyright © 2011, The Physiological Society|
|Appears in Collections:||Medicine publications|
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