The Role of ATP and Purinergic Receptors in Taste Signaling

Abstract

This review summarizes our understanding of ATP signaling in taste and describes new directions for research. ATP meets all requisite criteria to be considered a neurotransmitter: (1) presence in taste cells, as in all cells; (2) release upon appropriate taste stimulation; (3) binding to cognate purinergic receptors P2X2 and P2X3 on gustatory afferent neurons, and (4) after release, enzymatic degradation to adenosine and other nucleotides by the ectonucleotidase, NTPDase2, expressed on the Type I, glial-like cells in the taste bud. Importantly, double knockout of P2X2 and P2X3 or pharmacological inhibition of P2X3 abolishes transmission of all taste qualities. In Type II taste cells (those that respond to sweet, bitter, or umami stimuli), ATP is released non-vesicularly by a large conductance ion channel composed of CALHM1 and CALHM3, which form a so-called channel synapse at areas of contact with afferent taste nerve fibers. Although ATP release has been detected only from Type II cells, it is also required for the transmission of salty and sour stimuli, which are mediated primarily by the Type III taste cells. The source of the ATP required for Type III cell signaling to afferent fibers is still unclear and is a focus for future experiments. The ionotropic purinergic receptor, P2X3, is widely expressed on many sensory afferents and has been a therapeutic target for treating chronic cough and pain. However, its requirement for taste signaling has complicated efforts at treatment since patients given P2X3 antagonists report substantial disturbances of taste and become non-compliant.

Keywords: Adenosine triphosphate; Cough; Dysgeusia; EctoATPase; Geniculate ganglion; Ion channels; Purinergic receptors; Synapses; Taste buds.

Fig. 1

Above: Representative recordings from the chorda tympani nerve of WT and P2X2/3 double-KO mice. Responses to tastants are eliminated while responses to cool temperature remain. Below: Bar graph comparing response magnitudes for WT (Blue) and KO (Red) animals to the array of taste and non-taste stimuli tested. Adapted from Finger et al. (2005)

Fig. 2

Effect of topical application of AF-353 on chorda tympani nerve responses. A. Representative integrated chorda tympani nerve response to different tastants before and after (red) application of 1.1 mM AF-353. Responses to all tastants were totally abolished after a 10 min treatment with AF-353. Responses start recovering 30 min after a rinse with water, denoting a reversible effect of the antagonist (not shown). Taste stimuli were applied for 30 s (bar beneath recording) and rinsed for 50 s with water. B. Percentage of neural response remaining after application of AF-353 at various concentrations on the tongue for 10 min. As all qualities were similarly affected, responses to all qualities were averaged (means ± SD) for each concentration of AF-353 applied to the tongue. Increasing the concentration of AF-353 proportionally decreased taste responses to all qualities. Modified, with permission, from Vandenbeuch et al. (2015)

Fig. 3

Semi-schematic diagram of a channel synapse from a Type II taste cell (blue) onto a terminal of gustatory nerve fiber (green). CALHM1/3 channels are embedded in the taste cell membrane at the point of contact, closely apposed to the large, “atypical” mitochondrion with tubular cristae. When (1) the taste cell fires an action potential, the strong depolarization (2) gates open the CALHM1/3 channels to release ATP into the synaptic cleft where (3) it activates P2X receptors on the afferent nerve fiber to generate a neural action potential. Modified from Romanov et al. (2018)

Fig. 4

The role of 5-HT3A signaling in sour taste transmission. (a) Representative chorda tympani nerve recording to various concentrations of citric acid before and 15 min after (red) i.p. injection of the 5-HT3 antagonist ondansetron (ODS; 1 mg/kg). (b) Average chorda tympani responses in WT mice to various stimuli before and after injection of ODS. The responses to acids were, in general, significantly smaller after ODS treatment. Similar results were observed with 5-HT3A knockout mice (data not shown). Data are presented as mean ± SEM. Modified from Larson et al. (2015)

Fig. 5

A–C. Geniculate ganglion showing P2X2 (magenta) and P2X3 (green) immunoreactivity. Image is a maximum Z-projection of 12 optical sections through a ~ 16 μm tissue section. Scale bar = 100 μm. Brightness and contrast were adjusted linearly to preserve relative expression level information. D–E. Multiple populations of geniculate ganglion cells respond differently to AF-353. D. Change in fluorescence ratio of two ganglion cells in response to 10 μM ATP, 10 μM ATP with 10 μM AF-353 and 55 mM KCl. In the cell shown in the upper trace 10 μM AF-353 completely blocks the ATP response whereas it only blocks about 50% of the response in the cell shown in the lower trace. Drug application order was the same between top and bottom traces. E. Effect of various concentrations of AF-353 on ganglion cells of WT (circles; n = 19 cells), X2KO (diamonds; n = 7 cells), and X3KO; triangles; n = 7–9). WT cells were separated into two categories according to their response to ATP at 1 μM AF-353. Cells above the mean response were classified as “less sensitive” (closed circles) while cells below the mean response were classified as “more sensitive” (open circles). For WT, individual cells are represented as circles with straight lines connecting individual cells. For X2KO and X3KO symbols indicate means SEM. Asterisks indicate significance (p < 0.001 Mann–Whitney test between “more sensitive” and “less sensitive” cells). X2KO, P2X2KO; X3KO, P2X3KO; WT, wild-type. Adapted with permission from (Vandenbeuch et al. 2015)