Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 589, Issue 14, Pages 3575-3593Publisher
WILEY
DOI: 10.1113/jphysiol.2011.206789
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Funding
- National Health and Medical Research Council of Australia (NHMRC)
- NHMRC [508103, 1008100]
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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. Utilising whole cell patch clamping, we applied calibrated displacements to neurites of dorsal root ganglion (DRG) neurons in short-term culture and recorded mechanically activated currents termed intermediately (IAMCs), rapidly (RAMCs) or slowly adapting (SAMCs). 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. Seventy-three per cent of Trpa1(+/+) small-diameter neurons responding to the TRPA1 agonist allyl-isothiocyanate (AITC) displayed IAMCs 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 contribution to normal mechanosensation in a specific subset of DRG neurons. Furthermore, they also provide new evidence illustrating mechanisms by which sensitisation 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.
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