the sole sensor responsible for noxious cold responses in M+A+ LETTER neurons (1). However, TRPA1 is also activated by cooling and underlies at least part of the noxious cold responsiveness of Transient receptor potential channel AITC-sensitive neurons (3). Third, the authors used nicardipine 2+ promiscuity frustrates to selectively inhibit CaV1-type voltage-gated Ca channels (1). However, several dihydropyridines, including nicardipine, also constellation pharmacology act as TRPA1 agonists (4). These considerations led us to propose an alternative Sensory neurons from the trigeminal and dorsal root ganglia molecular interpretation of the difference between M+A− (DRG) have nerve endings in the skin and mucosa, where they and M+A+ neurons, which is in much better agreement with detect environmental stimuli and convey this information to published work. In accord with the authors, we conclude that the central nervous system. Several members of the transient M+A− neurons express TRPM8 but lack expression of receptor potential (TRP) superfamily of ion channels act as TRPA1. In contrast to the authors, we propose that M+A+ prime molecular sensors for thermal and chemical stimuli in neurons express TRPA1 as the prime cold and menthol these sensory neurons. However, it is incompletely understood sensor (2, 3). This interpretation is consistent with published how TRP channel expression and modulation affect the stimulus observations that menthol responses in M+A− but not in sensitivities of distinct neuronal subtypes. M+A+ neurons are inhibited by TRPM8 antagonists (5) In a recent article, Teichert et al. (1) described a “constellation and that TRPA1-mediated responses to cold in neurons are pharmacology approach” to identify and characterize subtypes characterized by a higher (colder) threshold (3). The para- of DRG neurons according to their responsiveness to a panel of doxical enhancement of cold responses in M+A+ neurons

pharmacological tools. In particular, they distinguished two in the presence of the CaV1 antagonist nicardipine may be neuronal subtypes of menthol-sensitive neurons, referred to as fully attributed to direct stimulation of TRPA1 by dihy- M+A− [i.e., menthol positive but ATP and allyl isothiocyanate dropyridines (4). (AITC) negative] and M+A+ (menthol, ATP, and AITC posi- This discussion reiterates the persistent need for more tive) neurons, which strongly differ in their sensitivity to cold specific TRP channel ligands, which are an absolute prerequisite and menthol and in their modulation by antagonists of voltage- for an unequivocal constellation pharmacology approach. gated channels. The authors concluded that TRPM8 is the Thomas Voets1, Karel Talavera, and Bernd Nilius sole functional cold and menthol sensor in both M+A− and Laboratory of Ion Channel Research and TRP Channel Research M+A+ neurons and that the striking difference in cold and Platform Leuven, University of Leuven, 3000 Leuven, Belgium menthol sensitivity between these neuronal subtypes is mainly due to differences in the constellation of voltage-gated Ca2+, 1. Teichert RW, et al. (2012) Characterization of two neuronal subclasses through Proc Natl Acad Sci USA – + + constellation pharmacology. 109(31):12758 12763. K , and Na channels (1). 2. Karashima Y, et al. (2007) Bimodal action of menthol on the transient receptor We argue that the authors’ interpretation of the molecular potential channel TRPA1. J Neurosci 27(37):9874–9884. Proc Natl fl 3. Karashima Y, et al. (2009) TRPA1 acts as a cold sensor in vitro and in vivo. origin of the observed responses is awed, owing to an Acad Sci USA 106(4):1273–1278. incomplete consideration of the promiscuity of the applied 4. Fajardo O, Meseguer V, Belmonte C, Viana F (2008) TRPA1 channels: Novel targets of 1,4-dihydropyridines. Channels (Austin) 2(6):429–438. pharmacological tools and thermal stimuli. First, the authors 5. Meseguer V, et al. (2008) Transient receptor potential channels in sensory neurons are considered menthol as a specific TRPM8 agonist (1). However, targets of the antimycotic agent clotrimazole. J Neurosci 28(3):576–586. earlier findings demonstrate that menthol also activates another

sensory TRP channel, the AITC-sensitive TRPA1, and that Author contributions: T.V., K.T., and B.N. wrote the paper. menthol excites AITC-sensitive neurons via TRPA1 rather The authors declare no conflict of interest. than via TRPM8 (2). Second, the authors considered TRPM8 as 1To whom correspondence should be addressed. E-mail: [email protected].

E3338 | PNAS | December 4, 2012 | vol. 109 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1213778109 Downloaded by guest on September 26, 2021