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A TRPA1-dependent mechanism for the pungent sensation of weak acids.

Wang YY, Chang RB, Allgood SD, Silver WL, Liman ER - J. Gen. Physiol. (2011)

Bottom Line: Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids.Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice.We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO(2), through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca(2+) microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca(2+)-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

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Responses of the trigeminal nerve to acetic acid cannot be attributed to changes in extracellular pH. (A) Diagram showing the method of stimulus delivery and position of the recording electrode. (B) Integrated nerve responses to acetic acid applied at increasing concentrations as indicated. (C) Relationship between the magnitude of the nerve response and the extracellular pH for each acid tested. Responses were normalized to the response to cyclohexanone applied immediately before and after exposure to each acid. Data represent the mean ± SEM.
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fig1: Responses of the trigeminal nerve to acetic acid cannot be attributed to changes in extracellular pH. (A) Diagram showing the method of stimulus delivery and position of the recording electrode. (B) Integrated nerve responses to acetic acid applied at increasing concentrations as indicated. (C) Relationship between the magnitude of the nerve response and the extracellular pH for each acid tested. Responses were normalized to the response to cyclohexanone applied immediately before and after exposure to each acid. Data represent the mean ± SEM.

Mentions: Previous experiments have showed that nerve fibers that innervate the nasal and oral cavities can be activated by weak acids (Silver and Moulton, 1982; Bryant and Moore, 1995), but whether this activity can be attributed to changes in extracellular pH or to the specific properties of weak acids has not been well defined. To investigate the receptor mechanisms that contribute to the irritant sensation produced by weak acids, we measured responses from the ethmoid nerve of the rat, a branch of the ophthalmic division of the trigeminal nerve, which innervates the anterior nasal cavity (Fig. 1 A). Test stimuli were delivered to the rat’s nasal cavity through a nasopharyngeal tube. The stimuli chosen were a series of carboxylic acids that differed in chain length: formic acid, acetic acid, and PA. HCl was used to test the effect of extracellular protons alone. Each acid was tested at increasing concentration (decreasing pH). Representative data shown in Fig. 1 B demonstrate that the response to acetic acid is robust and dose dependent. To compare responses across stimuli, we normalized the data to the response evoked by cyclohexanone and plotted the normalized response as a function of pH. As can be seen in Fig. 1 C, the response magnitude increased as the pH of the solution decreased for each acid tested. However, the relationship between pH and response magnitude was not invariant across acids; propionic and acetic acid elicited much larger responses than did formic acid or HCl at the same pH (approximately pH 4). In addition, we noted a trend for the response magnitude to increase as the chain length increased, suggesting that degree of membrane permeability may be a partial determinant of the response magnitude. Collectively, these data indicate that the irritating sensation produced by weak acids cannot be solely attributed to extracellular acidification.


A TRPA1-dependent mechanism for the pungent sensation of weak acids.

Wang YY, Chang RB, Allgood SD, Silver WL, Liman ER - J. Gen. Physiol. (2011)

Responses of the trigeminal nerve to acetic acid cannot be attributed to changes in extracellular pH. (A) Diagram showing the method of stimulus delivery and position of the recording electrode. (B) Integrated nerve responses to acetic acid applied at increasing concentrations as indicated. (C) Relationship between the magnitude of the nerve response and the extracellular pH for each acid tested. Responses were normalized to the response to cyclohexanone applied immediately before and after exposure to each acid. Data represent the mean ± SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105510&req=5

fig1: Responses of the trigeminal nerve to acetic acid cannot be attributed to changes in extracellular pH. (A) Diagram showing the method of stimulus delivery and position of the recording electrode. (B) Integrated nerve responses to acetic acid applied at increasing concentrations as indicated. (C) Relationship between the magnitude of the nerve response and the extracellular pH for each acid tested. Responses were normalized to the response to cyclohexanone applied immediately before and after exposure to each acid. Data represent the mean ± SEM.
Mentions: Previous experiments have showed that nerve fibers that innervate the nasal and oral cavities can be activated by weak acids (Silver and Moulton, 1982; Bryant and Moore, 1995), but whether this activity can be attributed to changes in extracellular pH or to the specific properties of weak acids has not been well defined. To investigate the receptor mechanisms that contribute to the irritant sensation produced by weak acids, we measured responses from the ethmoid nerve of the rat, a branch of the ophthalmic division of the trigeminal nerve, which innervates the anterior nasal cavity (Fig. 1 A). Test stimuli were delivered to the rat’s nasal cavity through a nasopharyngeal tube. The stimuli chosen were a series of carboxylic acids that differed in chain length: formic acid, acetic acid, and PA. HCl was used to test the effect of extracellular protons alone. Each acid was tested at increasing concentration (decreasing pH). Representative data shown in Fig. 1 B demonstrate that the response to acetic acid is robust and dose dependent. To compare responses across stimuli, we normalized the data to the response evoked by cyclohexanone and plotted the normalized response as a function of pH. As can be seen in Fig. 1 C, the response magnitude increased as the pH of the solution decreased for each acid tested. However, the relationship between pH and response magnitude was not invariant across acids; propionic and acetic acid elicited much larger responses than did formic acid or HCl at the same pH (approximately pH 4). In addition, we noted a trend for the response magnitude to increase as the chain length increased, suggesting that degree of membrane permeability may be a partial determinant of the response magnitude. Collectively, these data indicate that the irritating sensation produced by weak acids cannot be solely attributed to extracellular acidification.

Bottom Line: Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids.Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice.We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO(2), through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca(2+) microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca(2+)-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

Show MeSH
Related in: MedlinePlus