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Bimodal effects of cinnamaldehyde and camphor on mouse TRPA1
Yeranddy A Alpizar1, Maarten Gees, Alicia Sanchez
1Laboratory for Ion Channel Research and TRP Channel Research Platform, Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium.
Abstract:
TRPA1 is a nonselective cation channel activated by a wide variety of noxious chemicals. Intriguingly, several TRPA1 modulators induce a bimodal effect, activating the channel at micromolar concentrations and inhibiting it at higher concentrations. Here we report the bimodal action of cinnamaldehyde (CA) and camphor, which are thus far reported as agonist and antagonist of TRPA1, respectively. Whole-cell patch-clamp experiments in TRPA1-expressing CHO cells revealed that, as previously reported, extracellular application of 100 μM CA strongly stimulates TRPA1 currents. However, subsequent application of 3 mM CA induced fast and reversible current inhibition. Application of 3 mM CA in basal conditions induced a rather small current increase, followed by current inhibition and a dramatic rebound of current amplitude upon washout. These observations are reminiscent of the effects of TRPA1 modulators having bimodal effects, e.g., menthol and nicotine. In line with previous reports, extracellular application of 1 mM camphor induced a decrease of basal TRPA1 currents. However, the current amplitude showed a significant overshoot upon washout. On the other hand, application of 100 μM camphor induced a 3-fold increase of the basal current amplitude measured at -75 mV. The bimodal effects of CA and camphor on TRPA1 were also observed in microfluorimetric measurements of intracellular Ca(2+) in intact TRPA1-expressing CHO cells and in primary cultures of mouse dorsal root ganglion neurons. These findings are essential for the understanding of the complex sensory properties of these compounds, as well as their utility when used to study the pathophysiological relevance of TRPA1.
Insights
Cinnamaldehyde and camphor show dual effects on the TRPA1 channel, activating it at low doses and inhibiting it at high doses. This bimodal action influences sensory perception and TRPA1 channel research.
Area of Science:
- Molecular Biology
- Neuroscience
- Ion Channel Physiology
Background:
- Transient Receptor Potential Ankyrin 1 (TRPA1) is a key sensor for noxious stimuli.
- Some TRPA1 modulators exhibit concentration-dependent bimodal effects, activating at low and inhibiting at high concentrations.
Purpose of the Study:
- To investigate the bimodal action of cinnamaldehyde (CA) and camphor on the TRPA1 channel.
- To characterize the concentration-dependent effects of CA and camphor on TRPA1 activity.
Main Methods:
- Whole-cell patch-clamp electrophysiology in TRPA1-expressing CHO cells.
- Microfluorimetric measurements of intracellular calcium (Ca2+) in TRPA1-expressing cells and primary neurons.
Main Results:
- Cinnamaldehyde (CA) activated TRPA1 at 100 μM but inhibited it at 3 mM, with a rebound effect upon washout.
- Camphor inhibited TRPA1 at 1 mM but activated it at 100 μM, also showing a rebound.
- Bimodal effects were confirmed in both cell lines and primary dorsal root ganglion neurons.
Conclusions:
- Cinnamaldehyde and camphor display previously unreported bimodal concentration-dependent effects on the TRPA1 channel.
- These findings are crucial for understanding the complex sensory roles of these compounds and their use in TRPA1 research.
