Primary alcohols activate human TRPA1 channel in a carbon chain length-dependent manner.

Abstract

Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable non-selective cation channel that is mainly expressed in primary nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent compounds such as mustard oil and cinnamaldehyde, and intracellular alkalization. Here, we show that primary alcohols, which have been reported to cause skin, eye or nasal irritation, activate human TRPA1 (hTRPA1). We measured intracellular Ca(2+) changes in HEK293 cells expressing hTRPA1 induced by 1 mM primary alcohols. Higher alcohols (1-butanol to 1-octanol) showed Ca(2+) increases proportional to the carbon chain length. In whole-cell patch-clamp recordings, higher alcohols (1-hexanol to 1-octanol) activated hTRPA1 and the potency increased with the carbon chain length. Higher alcohols evoked single-channel opening of hTRPA1 in an inside-out configuration. In addition, cysteine at 665 in the N terminus and histidine at 983 in the C terminus were important for hTRPA1 activation by primary alcohols. Furthermore, straight-chain secondary alcohols increased intracellular Ca(2+) concentrations in HEK293 cells expressing hTRPA1, and both primary and secondary alcohols showed hTRPA1 activation activities that correlated highly with their octanol/water partition coefficients. On the other hand, mouse TRPA1 did not show a strong response to 1-hexanol or 1-octanol, nor did these alcohols evoke significant pain in mice. We conclude that primary and secondary alcohols activate hTRPA1 in a carbon chain length-dependent manner. TRPA1 could be a sensor of alcohols inducing skin, eye and nasal irritation in human.

• Authors: Tomoko Komatsu, Kunitoshi Uchida, Fumitaka Fujita, Yiming Zhou, Makoto Tominaga
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 463 Issue 4 Pg. 549-59 (Apr 2012) ISSN: 1432-2013 [Electronic] Germany
• PMID: 22222967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alcohols
• Calcium Channels
• Hexanols
• Nerve Tissue Proteins
• TRPA1 Cation Channel
• TRPA1 protein, human
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• 1-hexanol
• 1-Butanol
• 1-Octanol
• Calcium

Topics

• 1-Butanol (pharmacology)
• 1-Octanol (pharmacology)
• Alcohols (chemistry, pharmacology)
• Animals
• Calcium (metabolism)
• Calcium Channels (analysis, genetics, metabolism)
• Cell Line
• Cells, Cultured
• HEK293 Cells
• Hexanols (pharmacology)
• Humans
• Membrane Potentials (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Structure
• Mutation (genetics)
• Nerve Tissue Proteins (analysis, genetics, metabolism)
• Neurons (drug effects, metabolism)
• Patch-Clamp Techniques
• TRPA1 Cation Channel
• Transient Receptor Potential Channels (analysis, chemistry, drug effects, genetics, metabolism)