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

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 CO2, 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 Ca2+ 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 Ca2+-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.

Intracellular Proton-mediated Activation of TRPV3 Channels Accounts for the Exfoliation Effect of α-Hydroxyl Acids on Keratinocytes

“…Weak acids from normal cellular metabolites, whereas not toxic under physiological conditions, can lead to intracellular acidification in a concentration and extracellular pH-dependent fashion (12,43,(57)(58)(59). In this study, we demonstrated that glycolic acid-induced intracellular acidification could lead to TRPV3 activation.…”

The K + channel K IR 2.1 functions in tandem with proton influx to mediate sour taste transduction

“…Similar results were found in recordings from a slice preparation of lingual epithelium, where focal application of sour stimuli elicited calcium responses in taste cells that correlated with the degree of intracellular acidification (20) To our knowledge, our experiments are the first to directly show that intracellular acidification alone, in the absence of extracellular acidification, increases cellular excitability in identified sour taste cells. For these experiments, we used two organic weak acids, acetic acid and propionic acid, which due to their small size and relatively high pK a values (4.76 and 4.88, respectively) can acidify the cell cytosol when used at neutral pH (27). Application of these acids at neutral pH caused a similar degree of intracellular acidification in both TRPM5 and PKD2L1 cells, but only PKD2L1 cells fired action potentials.…”

“…The inward K + current (at −80 mV) was unaffected by lowering the pH of the extracellular solution (to pH 6.0), but was strongly inhibited by 20 mM acetic acid, pH 6.0, a condition that acidifies the cell cytosol (27) (Fig. 2 A and B).…”

“…1 A and B). To acidify the cell cytosol, we used acetic acid (AA) and propionic acid (PA), weak acids that partition in the lipid bilayer in their protonated form and are able to shuttle protons across the cell membrane (26)(27)(28). Each acid was used at a concentration of 100 mM and pH of 7.4, which generates ∼0.3 mM of the membrane permeable form.…”

Trigeminal Chemesthesis

“…Among the large family of transient receptor potential (TRP) ion-channels that includes the capsaicin (TRPV1) and menthol (TRPM8) receptors (Appendino et al, 2008;Inoue, 2005;Kim and Baraniuk, 2007;Woodard et al, 2007), the TRPA1 nociceptor has been implicated in the chemesthetic response to environmental irritants Macpherson et al, 2007b;McNamara et al, 2007) and even to CO 2 (Wang et al, 2010), as well as to weak organic acids (Wang et al, 2011). The TRPM5 channel has also been implicated in responses to irritants (Lin et al, 2008).…”