In the tongue, distinct classes of taste receptor cells detect the five basic tastes; sweet, sour, bitter, sodium salt and umami1,2. Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive and generally attractive to animals. By contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one3,4,5,6,7. This appetitive–aversive balance helps to maintain appropriate salt consumption3,4,6,8, and represents an important part of fluid and electrolyte homeostasis. We have shown previously that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaC8, but the cellular substrate for salt aversion was unknown. Here we examine the cellular and molecular basis for the rejection of high concentrations of salts. We show that high salt recruits the two primary aversive taste pathways by activating the sour- and bitter-taste-sensing cells. We also demonstrate that genetic silencing of these pathways abolishes behavioural aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways show unimpeded, continuous attraction even to very high concentrations of NaCl. We propose that the ‘co-opting’ of sour and bitter neural pathways evolved as a means to ensure that high levels of salt reliably trigger robust behavioural rejection, thus preventing its potentially detrimental effects on health.
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We thank E. Vitalis and N. Propp for the generation and maintenance of mouse lines, and K. Mueller for the construction of T2R-Sapphire lines. We also thank J. Chandrashekar, W. Sly and A. Waheed for advice and discussions, and K. Scott and members of our laboratories for comments. Y.O. was supported by the Japan Society for Promotion of Science. This research was supported in part by the intramural research program of the National Institutes of Health and National Institute of Dental and Craniofacial Research (to N.J.P.R.). C.S.Z. is an investigator of the Howard Hughes Medical Institute.
C.S.Z. is a scientific founder and scientific advisory board member of Senomyx.
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Oka, Y., Butnaru, M., von Buchholtz, L. et al. High salt recruits aversive taste pathways. Nature 494, 472–475 (2013). https://doi.org/10.1038/nature11905
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