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Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation
T G Banke1, S R Chaplan, A D Wickenden
1Johnson & Johnson PRD, LLC, Pain and Related Disorders, San Diego, CA 92121, USA. tbanke@gmail.com
American Journal of Physiology. Cell Physiology
|May 12, 2010
Summary
Transient Receptor Potential Ankyrin 1 (TRPA1) channels can dilate to allow large molecules through, a process regulated by calcium ions. This pore dilation may limit sensory neuron activation by irritants.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Transient Receptor Potential Ankyrin 1 (TRPA1) channels are expressed in sensory neurons and implicated in pain and inflammation.
- TRP channels are known to mediate various sensory stimuli.
Purpose of the Study:
- To investigate the mechanism of pore dilation in TRPA1 channels upon agonist stimulation.
- To determine the role of divalent cations, particularly calcium, in regulating TRPA1 channel permeability.
Main Methods:
- Patch-clamp electrophysiology to measure ion flux.
- Fluorescent dye uptake assays (Yo-Pro) to assess pore size.
- Application of various agonists and divalent cations.
- Testing the effect of gap junction/pannexin blockers.
Main Results:
- Agonist stimulation of TRPA1 and other TRP channels induces a large pore permeable to organic cations like Yo-Pro.
- This pore dilation is dependent on the agonist and divalent cations.
- The process is reversible and mediated by changes in the TRP channel selectivity filter, not gap junctions.
- External calcium ions regulate the duration of the dilated state.
Conclusions:
- TRPA1 channels undergo a calcium-regulated, reversible pore dilation process.
- This dilation mechanism allows passage of large organic cations and may limit sensory neuron overactivation.
- Calcium ions play a novel role in modulating TRP channel states and sensory neuron responses.
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