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Review

Differential Effect of TRPV1 Modulators on Neural and Behavioral Responses to Taste Stimuli

by
Mee-Ra Rhyu
1,
Mehmet Hakan Ozdener
2 and
Vijay Lyall
3,*
1
Department of Food Science and Biotechnology, Sejong University, Seoul 05006, Republic of Korea
2
Monell Chemical Senses Center, Philadelphia, PA 19104, USA
3
Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, USA
*
Author to whom correspondence should be addressed.
Nutrients 2024, 16(22), 3858; https://doi.org/10.3390/nu16223858
Submission received: 13 October 2024 / Revised: 6 November 2024 / Accepted: 9 November 2024 / Published: 12 November 2024
(This article belongs to the Special Issue The Importance of Taste on Dietary Choice: Modulation of Taste Sensitivity)
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Abstract

:
In our diet, we ingest a variety of compounds that are TRPV1 modulators. It is important to understand if these compounds alter neural and behavioral responses to taste stimuli representing all taste qualities. Here, we will summarize the effects of capsaicin, resiniferatoxin, cetylpyridinium chloride, ethanol, nicotine, N-geranyl cyclopropylcarboxamide, Kokumi taste peptides, pH, and temperature on neural and behavioral responses to taste stimuli in rodent models and on human taste perception. The above TRPV1 agonists produced characteristic biphasic effects on chorda tympani taste nerve responses to NaCl in the presence of amiloride, an epithelial Na+ channel blocker, at low concentrations enhancing and at high concentrations inhibiting the response. Biphasic responses were also observed with KCl, NH4Cl, and CaCl2. In the presence of multiple stimuli, the effect is additive. These responses are blocked by TRPV1 antagonists and are not observed in TRPV1 knockout mice. Some TRPV1 modulators also increase neural responses to glutamate but at concentrations much above the concentrations that enhance salt responses. These modulators also alter human salt and glutamate taste perceptions at different concentration ranges. Glutamate responses are TRPV1-independent. Sweet and bitter responses are TRPV1-independent but the off-taste of sweeteners is TRPV1-dependent. Aversive responses to acids and ethanol are absent in animals in which both the taste system and the TRPV1-trigeminal system are eliminated. Thus, TRPV1 modulators differentially alter responses to taste stimuli.

1. Introduction

Among members of the transient receptor potential cation channel family, the least amount of information is available on the role of transient receptor potential vanilloid type 1 channel (TRPV1) in taste [1,2]. This is partly due to the fact that TRPV1 expression in taste receptor cells (TRCs) is species-dependent. TRPV1 is not expressed in rodent TRCs but it is expressed in human taste cells [3,4]. In addition, TRPV1 modulators produce varying effects on different taste nerves to taste stimuli depending upon the taste receptive field being stimulated [5]. TRPV1 is highly expressed in trigeminal nerves surrounding the taste buds [2]. TRPV1 expressed in a subset of TRCs can potentially directly interact with a specific taste quality. Alternately, TRPV1 expressed in the trigeminal nerves can contribute to the aversive responses to some taste stimuli [6]. Activation of TRPV1 in trigeminal nerves can indirectly alter specific taste responses by releasing peptides (substance P and calcitonin gene-related peptide) [7]. The aim of this review is to first describe the taste transduction mechanism of each taste quality and then summarize the effect of TRPV1 modulators on neural and behavioral responses to taste stimuli representing all taste qualities. In our diet, we ingest a variety of compounds that are potential TRPV1 modulators. Therefore, it is important to understand how these compounds affect taste responses to salty, sweet, umami, bitter, and sour stimuli. Some TRPV1 modulators can be useful in devising strategies to decrease excessive consumption of high salt, ethanol, and nicotine.

TRPV1

TRPV1 is a polymodal non-selective cationic channel. It is a tetrameric protein made up of four monomers, with each monomer harboring six transmembrane segments (S1–S6) with cytoplasmic C- and N-terminal domains and a pore region between the S5 and S6 domains [8]. A large number of ligands activate the channel exogenously and endogenously. These include capsaicin (Cap), resiniferatoxin (RTX), piperine, gingerol, zingerone, camphor, eugenol, ethanol, some toxins in venom, noxious temperatures (>43 °C), acid pH, divalent cations (Mg2+ and Ba2+), N-arachidonoylethanolamine (anandamide), 2-arachidonoylglycerol, N-arachidonoyl dopamine, N-oleoyldopamine, ATP, lipoxygenase products, and monoacylglycerols. When multiple stimuli are presented together, TRPV1 activation is potentiated. TRPV1 is expressed in neurons and glial cells, and in non-neuronal tissues, such as heart, liver, lung, kidney, adipose tissue, skeletal muscle, and intestine. Upon activation, the channel allows Na+ and Ca2+ influxes that depolarize cells [9]. TRPV1 is regulated by intracellular adenosine-5′-triphosphate (ATP), phosphoinositides [10], protein kinas A (PKA) [11], and Ca2+ [12]. In cells expressing TRPV1 and transient receptor potential ankyrin 1 (TRPA1) ion channel, TRPA1 modulators may also augment TRPV1 activity [13].

2. Effect of TRPV1 Modulators on Neural and Behavioral Response to Sour Taste Stimuli

Sour taste is elicited by acidic stimuli and produces an aversive response. Recordings of the rat chorda tympani (CT) taste nerve, while the anterior fungiform receptive field was under lingual voltage-clamp, revealed that HCl responses are voltage-sensitive [14]. Relative to zero current clamp, the magnitude of the HCl CT response increased at −90 mV and decreased at +90 mV. Zn2+ inhibited the HCl CT response in a concentration-dependent manner, and eliminated the voltage sensitivity (±90 mV) of the response. Zn2+ only partially inhibited the CT response to H3PO4 but did not inhibit response to acetic acid. HCl and H3PO4 generate H+ externally while acetic acid is membrane-permeable and decreases TRC pHi. Increasing TRC cAMP in vivo increased the magnitude of the HCl CT response that demonstrated voltage dependence over all voltages between +90 mV and −90 mV [14]. These results suggested that, in the fungiform taste receptive field, a Zn2+-sensitive proton channel that is activated by cAMP is involved in the detection of H+ in TRCs.
Polycystin-2-like 1 (PKD2L1) channel is expressed exclusively in type III TRCs in the mouse. Animals in which PKD2L1-expressing cells in the taste buds were eliminated did not elicit neural responses to sour taste stimuli [15,16]. However, mice lacking PKD2L1 and/or polycystin-1-like-3 or transient receptor potential channel (PKD1L3), still demonstrated robust taste responses to acids [17,18]. This indicated that PKD2L1/PKD1L3 channels are markers of type III TRCs but are not involved in detecting sour taste stimuli. The search for the elusive proton channel was upended by two research groups by demonstrating the expression and function of Otopetrin-1 (OTOP1), a proton-selective channel, in PKD2L1-positive TRCs [19]. OTOP1 is required for a decrease in pHi in Type III TRCs and is inhibited by Zn2+. This indicates that a decrease in TRC pHi is the proximate signal for sour taste transduction [20].
Sour-sensing cells also detect CO2. CT responses to CO2 are voltage sensitivity. Compared with open-circuit conditions, CO2 CT responses were enhanced at −60 mV and suppressed at +60 mV [20]. CO2-induced decrease in TRC pHi and CT response were inhibited by membrane-permeable blockers of carbonic anhydrases, MK-417 and MK-927. In subsequent studies, carbonic anhydrase-4 (Car4) was identified in type III TRCs expressing PKD2L1 and OTOP1 [6,21]. Car4 KO mice had significantly diminished CT response to CO2. Most importantly, when tetanus toxin light chain was trans-genetically targeted to type III TRCs, it not only prevented the neurotransmitter release from these TRCs but also selectively and completely abolished responses to sour stimuli and CO2 [21]. Prodynorphin-expressing sour-responding neurons in the rostral nucleus of the solitary tract receive direct and selective input from Proenkephalin (Penk)-expressing sour ganglion neurons that, in turn, receive input from type III cells [6]. Thus, a subset of TRCs and ganglion cells are dedicated to sour taste sensing.
Stimulating with HCl containing RTX, a potent capsaicin-like TRPV1 agonist, did not alter rat CT responses to HCl [22]. I-RTX (a high affinity TRPV1 antagonist) also did not affect mouse CT responses to acetic acid, citric acid, and HCl but significantly suppressed mouse GL responses to the above acids. Mouse SL nerve responded in a concentration-dependent manner to the above acids. The responses to acetic acid, but not to the other acids were inhibited by I-RTX. These results suggested that TRPV1 is likely involved in responses to acids in the posterior oral cavity and larynx. This high degree of responsiveness to acetic acid may be responsible for the oral burning sensation of vinegar [5].
Genetic ablation of PKD2L1-expressing TRCs or generating OTOP1 KO mice did not alter the aversive behavior of mice to acids. In OTOP1 KO mice in which trigeminal TRPV1 neurons were ablated, mice exhibited a major loss of behavioral aversion to acid [6]. Thus, the trigeminal system and the taste system work in concert to evoke aversive responses to acids. However, CO2 responses are entirely dependent upon type III cells [21]. CO2 specifically activates a subpopulation of trigeminal neurons that expresses TRPA1 but does not activate TRPV1 [23].

3. Effect of TRPV1 Modulators on Neural and Behavioral Responses to NaCl, KCl, NH4Cl, and CaCl2

3.1. TRPV1 and Taste Responses to NaCl

Salt taste is transduced by an amiloride (Am)-sensitive pathway that is Na+-specific and an Am-insensitive pathway that is cation non-selective. TRPV1 modulators differentially alter both salt-sensing pathways in humans and rodent models.

3.2. TRPV1 and ENaC-Dependent Na+-Specific Salt Taste

Am-sensitive Na+-specific salt taste is detected by a subset of Type II fungiform TRCs that express αENaC (epithelial Na+ channel), phospholipase C β2 (PLCβ2), IP3 (inositol triphosphate), CALHM3 (Ca2+ homeostasis modulator 3), and a transcription factor skin head, SKN-1a. These cells do not express TRPM5 (Transient Receptor Potential Cation Channel Subfamily M Member 5) and GNAT3 (guanine nucleotide-binding protein G(t) subunit alpha-3). Na+ entry through ENaC induces a suprathreshold depolarization for action potentials driving voltage-dependent, Ca2+-independent neurotransmitter release via the CALHM1/3 channel synapse [24,25,26]. ENaC is composed of α, β, and γ subunits but these subunits have segregated expression in mouse taste buds. Thus, the exact subunit composition of the functional ENaC channels in rodent TRCs is unclear [27]. In geniculate ganglia, Early growth response protein 2 (Egr2)-expressing neurons receive input from cells that detect appetitive NaCl concentrations [6]. Thus, appetitive salt responses are detected by dedicated TRCs and geniculate ganglia neurons [28].
In contrast to rodent TRCs [2], TRPV1 mRNA was detected in cultured human taste cell lysates [3]. In human fungiform taste cells (HBO cells) [4], TRPV1 mRNA expression and TRPV1 antibody was localized in HBO cells expressing δ-ENaC subunits and δ-ENaC subunits co-localized with gustducin and PLCβ2. Both α-ENaC and γ-ENaC subunits also co-localized with PLCβ2. The δ-ENaC subunit expressing HBO cells also expressed components of the renin–angiotensin–aldosterone system (RAAS) and G-protein-coupled estrogen receptor, signaling molecules that regulate ENaC expression and taste responses to NaCl [29,30,31]. Some ENaC regulators are most likely present in a complex and changes in the expression of one or more regulators can alter the expression of other effectors. Culturing HBO cells in media containing high salt induced an increase in δ-ENaC mRNA and protein and decreased TRPV1 mRNA expression. On the other hand, culturing them in media containing 2.5 μM Cap increased the expression of TRPV1 [4]. In kidney cortical collecting duct cells, both high salt and Cap modulate TRPV1-dependent ENaC expression [32]. As summarized in Figure 1, high salt inhibits and Cap activates TRPV1 and alters [Ca2+]i. Downstream from [Ca2+]i, several intracellular signaling components are either inhibited or activated that modulate ENaC expression [32]. Polymorphisms of the TRPV1 gene are associated with alterations in salty taste sensitivity and salt preference [33]. Human salt-sensing TRCs express TRPV1 and δ-ENaC subunit. The effect of Cap in mitigating high salt-induced changes in ENaC expression in human taste cells may be relevant in reducing salt intake in humans [34,35]. Acutely stimulating with NaCl solutions containing Cap or RTX does not produce effects on the Am-sensitive NaCl CT response [22]. In HBO cells, Arginyl dipeptides increase the frequency of NaCl-elicited responses via ENaC α and δ subunits in HBO cells [36] and enhance saltiness of 50 mM NaCl in human sensory evaluation [37].
In some human subjects, lingual surface potential induced by oral NaCl was sensitive to Am and quantitatively correlated with the perceived salt taste intensity [38]. These studies support the role of ENaC in human salt taste. However, it is not clear if ENaC is the predominant salt taste receptor in humans and its contribution to overall human salt taste is difficult to evaluate [39]. In human lingual epithelium, δ subunit expression is much smaller compared to the expression of other subunits (α = β > γ » δ) [40], raising a question regarding the variability of the Am-sensitive and Am-insensitivity components of the human salt taste responses.

4. TRPV1 and Am-Insensitive and Cation Non-Selective Pathway That Detects NaCl, KCl, NH4Cl, and CaCl2

A variety of compounds with very different structures modulate Am-insensitive salt responses in rodent models (Table 1).

4.1. Cap, RTX, pH, and Temperature

TRPV1 modulators alter neural responses to NaCl, KCl, NH4Cl, and CaCl2 [5]. I-RTX (1–100 nM), a potent TRPV1 antagonist, decreased mouse CT responses to NaCl, KCl, and NH4Cl. In the GL nerve, I-RTX significantly suppressed responses to all salts. In the SL nerve, I-RTX did not inhibit responses to the above salts. In the CT nerve, I-RTX can alter NaCl responses via Am-sensitive and/or Am-insensitive pathways, while in the GL nerve the effects of I-RTX most likely are restricted to its effect on the Am-insensitive pathway(s). The observation that I-RTX suppressed responses to NaCl in both CT and GL nerves suggests that TRPV1 is directly or indirectly involved in regulating salt responses in rodents [5].

4.1.1. Biphasic Effects on NaCl CT Responses

Cap (or RTX) when mixed with the NaCl stimulus did not alter the magnitude of the Am-sensitive, ENaC-dependent component of rat NaCl CT response [22]. In the presence of Am or benzamil (Bz; a more potent blocker of ENaC), adding Cap (5–200 μM) or RTX (0.1–10.0 μM) produced a biphasic response in rat NaCl CT response. CT response was enhanced at low concentrations, and at high concentrations the response decreased from its maximum value. Cap and RTX increased the maximum CT response by more than 200%. At the highest concentrations used, the response decreased to baseline (Table 1). Capsazepine (CZP) and N-(3-methoxyphenyl)-4-chlorocinnamide (SB-366791), TRPV1 antagonists, inhibited the effects of Cap and RTX. The Am-insensitive NaCl CT responses are voltage-sensitive and the voltage sensitivity increased in the presence of RTX concentrations that enhanced the CT response.
Varying temperature between 23 °C and 55.5 °C produced a biphasic effect on the Am-insensitive NaCl CT responses, with maximum enhancement obtained at 42 °C (Table 1). RTX increased the CT response at 23 °C and shifted the temperature curve to the left in a dose-dependent manner. In the absence of RTX, the Am-insensitive NaCl CT responses were not sensitive to changes in the pH of the stimulating solutions (pH 2–10) but in the presence of RTX demonstrated a bell-shaped curve as a function of pH (Table 1) [22]. The Am-insensitive NaCl CT responses were regulated by phosphatidylinositol 4,5-bisphosphate (PIP2) [41], intracellular Ca2+, protein kinase C, and calcineurin [42]. An increase in intracellular PIP2 inhibited the control CT response and decreased its sensitivity to RTX. On the other hand, a decrease in intracellular PIP2 enhanced the control Am-insensitive NaCl CT response, increased its sensitivity to RTX stimulation, and inhibited the desensitization of the CT response at high RTX concentrations [41].
In TRPV1 KO mice, Bz inhibited the NaCl CT response to baseline [43]. TRPV1 KO mice did not elicit an increase in the Am-insensitive CT responses above the rinse baseline value at all RTX concentrations tested [41]. It was previously hypothesized that the Am-insensitive channel is a variant of TRPV1 (TRPV1t). However, TRPV1 is not expressed in rodent TRCs. Thus, at present, the identity of this channel in the fungiform-receptive field remains unknown.
In behavioral assay, wildtype and TRPV1 KO mice in the absence and presence of Am did not show any differences in their responses to NaCl [43]. In hindsight, this is not so surprising, as inhibition of CT nerve responses to some taste stimuli do not always correlate with the behavioral responses in animals [6,19,44]. Am-insensitive NaCl responses have been suggested to reside in subsets of bitter, sour, and sweet cells [45,46,47,48] and, thus, may involve several different receptors and pathways.

4.1.2. Biphasic Effects on KCl, NH4Cl, and CaCl2 CT Responses

Cap and RTX also produced similar biphasic effects on CT response to KCl, NH4Cl, and CaCl2, suggesting that this conductive pathway is a non-specific cation channel that allows Na+, K+, NH4+, and Ca2+ ion flux across the channel [22].
At present, it is not clear how TRPV1 agonists and antagonists modulate the Am-insensitive responses in rodent TRCs in the absence of TRPV1 expression. One possibility that needs to be further explored is that the activation of TRPV1 in trigeminal nerves may indirectly alter Am-insensitive NaCl taste receptors in sweet, bitter, or salty cells by releasing substance P and calcitonin gene-related peptide [7]. Calcitonin gene-related peptide can then act on the calcitonin gene-related peptide receptor expressed in Type III cells, that, presumably, also harbor the Am-insensitive salt taste receptor(s) [45,46].
Human salt taste is largely Am-insensitive [39,49,50]. In part, this is due to the expression of an additional ENaC subunit, the δ subunit, and the observation that, unlike the αβγ ENaC channel, the δβγ ENaC channel is Am-insensitive [51].
More recently, OTOP1 has been shown to be involved in NH4Cl sensing [52]. It is suggested that NH4Cl taste may be a distinct taste from the five primary taste qualities. Zn2+ inhibited CT nerve responses to NH4Cl in a dose-dependent manner. Gustatory nerve responses to NH4Cl were strongly attenuated or eliminated in OTOP1 KO mice. In polarized rat taste bud cells, apical NH4Cl produces intracellular alkalinization. In HEK-293 cells co-transfected with mOTOP1 and pHlourin, a pH-sensitive variant of green fluorescent protein, NH4Cl induced an increase in pHi paralleling its ability to evoke OTOP1 currents. Aversion of mice to NH4Cl was diminished in Skn-1a KO mice lacking Type II TRCs, but was entirely abolished in a double KO mouse model with OTOP1. Although TRPV1 is activated by intracellular alkalinization following exposure to NH4Cl/NH3 [53], the aversive NH4Cl response is not dependent upon the trigeminal system and resides entirely in Type II and Type III cells.

4.2. N-Geranyl Cyclopropyl-Carboxamide (NGCC)

NGCC enhanced Ca2+ influx in hTRPV1-expressing cells in a dose-dependent manner that was significantly attenuated by ruthenium red (RR), a non-specific blocker of TRP channels, and CZP, a specific antagonist of TRPV1, implying that NGCC directly activates hTRPV1 [54]. NGCC enhanced rat CT response to NaCl+Bz between 1 and 2.5 μM and inhibited it above 5 μM (Table 1). In the presence of a TRPV1 blocker, SB-366791, both NaCl+Bz and NaCl+Bz+NGCC CT responses were inhibited to baseline. No NaCl+Bz CT response was observed in TRPV1 KO mice in the absence or presence of NGCC. NGCC enhanced human salt taste intensity of fish soup stock containing 60 mM NaCl at 5 and 10 μM and decreased it at 25 μM [55]. Thus, both neural and behavioral responses to NGCC are biphasic.

4.3. Ethanol and Nicotine

At concentrations < 50%, ethanol enhanced CT responses to KCl and NaCl+Bz, while at ethanol concentrations > 50%, the CT responses were inhibited (Table 1). RTX and elevated temperature increased the sensitivity of the CT response to ethanol in salt-containing media, and SB-366791 inhibited the effect of ethanol, RTX, and elevated temperature on the CT responses. TRPV1 KO mice demonstrated no Bz-insensitive NaCl CT response and no sensitivity to ethanol [56].
At concentrations < 0.015 M, nicotine enhanced and at >0.015 M inhibited CT responses to KCl and NaCl+Bz (Table 1). Nicotine produced maximum enhancement in the NaCl+Bz CT response at pHo between 6 and 7. RTX and elevated temperature increased the sensitivity of the CT response to nicotine in salt-containing media, and SB-366791 inhibited these effects. TRPV1 KO mice demonstrated no NaCl+Bz CT response and no sensitivity to nicotine, RTX, and elevated temperature [57]. At pHo > 8, the apical membrane permeability of nicotine was increased significantly, resulting in increase in TRC pHi and volume, activation of ENaC, and enhancement of the Am-sensitive NaCl CT response. At pHo > 8, nicotine also inhibited the phasic component of the HCl CT response. These results suggest that the effects of nicotine on ENaC and the phasic HCl CT response arise from increase in TRC pHi and volume.

4.4. Kokumi Peptides

Maillard-reacted peptides (MRPs) are generated during cooking a wide range of foods containing proteins/peptides and carbohydrates. During cooking, covalent bonds between carbonyl groups and free amino groups are formed. Kokumi peptides include γ-glutamate (Glu), and other peptides containing γ-Glu such as γ-Glu-Ala, γ-Glu-Val, γ-Glu-Cys, γ-Glu-aminophenyl-Gly, and γ-Glu-Val-Gly [58,59,60,61]. These peptides activate calcium-sensing receptor (CaSR) [62] expressed in a subset of taste bud cells. CaSR is activated by cations (Ca2+ and Gd3+), peptides, and polyamines and transmits its signal through Gαq/11 proteins, PLCβ, and release of [Ca2+]i via activation of IP3 receptor channels in the endoplasmic reticulum. CaSR is inhibited by NPS-2143 [63].
MRPs and γ-glutamyl peptides also modulate salty taste [64,65]. We synthesized MRPs by conjugating a peptide fraction (1000–5000 Da) purified from soy protein hydrolysate with galacturonic acid (GalA), glucosamine, xylose (Xyl), fructose, or glucose [66]. In mixtures containing NaCl, MRPs did not alter the Am-sensitive NaCl CT responses. In a patch-clamp study on rat fungiform taste cells, kokumi-active tripeptides, glutathione, and γ-Glu-Val-Gly did not alter ENaC activity in taste cells [67].
In contrast, GalA-MRP added to NaCl+Bz stimulating solution increased the CT response between 0.1% and 0.25% and inhibited it above 0.5% (Table 1). The effectiveness of MRPs as salt taste enhancers varied with the conjugated sugar moiety: galacturonic acid = glucosamine > xylose > fructose > glucose. Elevated temperature, RTX, capsaicin, and ethanol produced additive effects on the NaCl CT responses in the presence of MRPs. SB-366791 inhibited the NaCl+Bz CT response in the absence and presence of MRPs. TRPV1 KO mice demonstrated no Am-insensitive NaCl CT response in the absence or presence of MRPs [66].
The concentrations at which MRPs enhanced human salt taste were significantly lower. In human subjects, between 0.0025% and 0.01%, both GalA-MRP and Xyl-MRP increased, and above 0.01% suppressed the salt taste intensity. In the presence of 0.01% GalA-MRP and Xyl-MRP, the median effective salt concentration was maximally enhanced by 5.9% and 3.5%, respectively. The increase in salt intensity in the presence of GalA-MRP was also enhanced at 45 °C relative to 30 °C. In mixtures containing 0.01% GalA-MRP+4% ethanol, the perceived salt intensity was greater than that of 4% ethanol alone. However, the perceived salt taste intensity was less than that of GalA-MRP alone. Thus, in the presence of MRPs, elevated temperature and ethanol alter human salt taste perception [66].
Kokumi taste-active and -inactive peptide fraction (500–10,000 Da) were isolated from mature (FIIm) and immature (FIIim) Ganjang, a typical Korean soy sauce. Only FIIm (0.1–1.0%) produced a biphasic effect in rat CT responses to NaCl+Bz (Table 1). Both elevated temperature (42 °C) and FIIm produced synergistic effects on the NaCl+Bz CT response. At 0.5%, FIIm produced the maximum increase in NaCl+Bz CT response and enhanced salt taste intensity in human subjects [64].
In mice, adding increasing concentrations of FIIm (0.1 to 1%) to 100 mM NaCl solutions in the absence and presence of 10 µM Am produced biphasic changes in NaCl preference, increasing it at 0.25% and lowering it at higher concentrations. FIIm maximally enhanced NaCl preference at 0.25% relative to NaCl alone and above 0.25% FIIm was significantly less than its maximum value. In the presence of 10 µM Am, the maximum increase in NaCl preference was observed at 0.5% FIIm and above 0.5% FIIm was significantly less than its maximum value. There was no change in NaCl preference when equivalent concentrations of the FIIim were added to the test solutions containing 100 mM NaCl or 100 mM NaCl+10 µM Am. These behavioral responses to NaCl correlate with the biphasic effects of FIIm concentrations on Am-insensitive NaCl CT responses [64].
Similar to hTRPV1, NGCC enhanced Ca2+ influx in hTRPA1-expressing cells (EC50 = 83.65 µM). NGCC-induced Ca2+ influx in hTRPA1-expressing cells was blocked by ruthenium red and 2-(1,3-dimethyl-2,6-dioxopurin-7-yl)-N-(4-propan-2-ylphenyl)acetamide (HC-030031), a specific antagonist of TRPA1 [54]. These studies suggest that some of effects of the above compounds on NaCl may involve additional ion channels.

4.5. Novel Salty and Salt-Enhancing Peptides

As reviewed recently [68], some peptides derived from various food proteins can elicit salt taste themselves in the absence of Na+, while a class of salt taste-enhancing peptides can increase salt taste perception, but they by themselves do not have an intrinsic salt taste. Using papain to hydrolyze Harpadon nehereu (a species of lizardfish) proteins produced salty peptides that elicited salt taste intensity equivalent to that of 50 mM NaCl solution [69]. Using papain and Neutrase to hydrolyze Parapenaeopsis hardwickii (Spear shrimp) proteins produced salty peptides that had saltiness intensity equivalent to that of 10 mM and 55 mM NaCl, respectively [70]. Salty peptide fractions isolated from the protein hydrolysate of bovine bone when used in the range of 0.1–0.5 g/100 mL, produced saltiness intensity that was higher than that of NaCl at the same concentration [71]. Salty dipeptides (Ile-Gln, Pro-Lys, Ile-Glu, Thr-Phe, and Leu-Gln) have been identified in soy sauce [72]. In yeast extract, several salty peptides (Asp-Asp, Glu-Asp, Asp-Asp-Asp, Ser-Pro-Glu, and Phe-Ile) have been identified that also exhibit salt taste-enhancing effects [73]. In Chinese fermented soybean curds, four decapeptides were found to be the main taste-active compounds. A decapeptide (Glu-Asp-Glu-Gly-Glu-Gln-Pro-Arg-Pro-Phe) had the strongest salt taste-enhancing effect [74]. At present, the cellular mechanism and receptors that these peptides activate have not been elucidated.

5. Effect of TRPV1 Modulators on Neural and Behavioral Responses to Bitter, Sweet, and Umami Taste Stimuli

Bitter taste is detected by a subset of TRCs that express about 30 different G-protein coupled receptors, taste receptors type 2 (TAS2Rs). Sweet and umami tastes are detected by different subsets of TRCs that express G-protein-coupled taste receptors that are heterodimers of TAS1R2+TAS1R3 and TAS1R1+TAS1R3, respectively. Umami receptor is not only activated by glutamate, but this activation is strongly enhanced in the presence of 5′- ribonucleotides. The above receptors are coupled to the G-protein gustducin and require downstream signaling effectors PLCβ2, IP3R3, TRPM5/TRPM4, and voltage-gated ATP release heterooligomeric channel composed of CALHM1 and CALHM3 [63,75,76]. In addition, Na+-glucose symporter-1 is implicated in (TAS1R2+TAS1R3)-independent sugar sensing [77,78,79,80].
In geniculate ganglia, Cadherin (Cdh13)-expressing neurons receive information from bitter-sensing cells, Cdh4-expressing neurons receive information from umami-sensing cells, and Spondin1-expressing neurons receive information from sweet-tasting cells [6]. Bitter ganglion neurons connect to bitter taste receptor cells expressing Semaphorin 3A and sweet ganglion neurons connect to sweet taste receptor cells expressing Semaphorin 7A [75]. These data provide strong evidence that bitter, sweet, and umami taste are transduced via a labeled line. Thus, generation of different types taste cells from stem cells in the taste bud and their connections to specific ganglion cells are regulated by transcription factors [81].

5.1. TRPV1 and Bitter Taste

Genetic variation in TRPV1 and TAS2Rs influences ethanol sensations and may potentially influence how individuals initially respond to alcoholic beverages [82]. Activation of TAS2Rs augments capsaicin-evoked TRPV1 responses in rat pulmonary nociceptors involving phospholipase C and protein kinase C signaling pathway [83]. Trigeminal fibers associated with thermo-sensation and pain communicate with parabrachial taste neurons. This multisensory convergence is involved in interactions between gustatory and somatosensory hedonic representations in the brain [84].
Stimulating with quinine–HCl (10 mM) solutions containing RTX (1 or 10 μM), did not alter CT responses to quinine [22]. Similarly, quinine–HCl solutions containing I-RTX (1–100 nM) did not alter responses in CT, GL, and SL nerves [5].
Quinine is a representative bitter compound and its taste responses are entirely dependent upon the TAS2R-TRPM5 pathway. Similar to quinine, nicotine and ethanol are bitter and elicit an aversive response. In behavior studies, quinine was not aversive to TRPM5 KO mice, but nicotine was equally aversive in wildtype and TRPM5 KO mice. TRPM5 KO mice still showed residual CT responses to nicotine that were blocked by a nAChR antagonist, mecamylamine. In contrast to quinine, nicotine elicits taste responses through peripheral TRPM5-dependent pathways, common to other bitter tastants, and a nAChR-dependent and TRPM5-independent pathway [44]. The nAChRs are expressed in TRPM5-positive cells [85]. The taste of nicotine and mecamylamine mixtures was more similar to the taste of quinine than that of nicotine alone [44].
Nicotine activates Cap-sensitive trigeminal neurons [86,87]. To test if aversive responses to nicotine are dependent upon the trigeminal system, we injected Cap in neonate TRPM5 KO mice to produce systemic and life-long elimination of the majority of Cap-sensitive neurons [88]. Although responses to Cap solutions confirmed the treatment was effective, preference for 0.5- and 1.0-mM nicotine did not differ between untreated and Cap-treated KO animals. Thus, in addition to the TRPM5-dependent pathway, nAChRs serve as bitter taste receptors for nicotine [89,90], and the aversive response to nicotine is purely taste-mediated and is independent of the trigeminal system in the oral cavity.
In TRPM5 knockout (KO) mice, nAChR modulators (mecamylamine, dihydro-β-erythroidine, and CP-601932 (a partial agonist of the α3β4* nAChR)) inhibited CT responses to nicotine, ethanol, and acetylcholine. This suggests that nAChRs expressed in a subset of TRCs serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine, and ethanol [91].
Sensory neurons from trigeminal or dorsal root ganglia as well as TRPV1-expressing HEK293 cells responded to ethanol in a concentration-dependent manner and are capsazepine-sensitive. Ethanol potentiated the response of TRPV1 to Cap, protons, and heat and lowered the threshold for heat activation of TRPV1 from approximately 42 °C to approximately 34 °C [92]. TRPV1 KO mice showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wildtype littermates [93]. They also displayed reduced oral avoidance responses to ethanol regardless of concentration, insensitivity to Cap, and little to no difference in sweet or bitter taste responses relative to wildtype mice. These data indicate that TRPV1 plays a role in orosensory-mediated ethanol avoidance [94].

5.2. TRPV1 and Sweet Taste

Stimulating with sucrose (500 mM) containing RTX (1 or 10 μM) did not alter CT responses to sucrose [22]. Sucrose solutions containing I-RTX (1–100 nM) did not alter responses in CT, GL, and SL nerves [5]. Sweet taste receptor (T1R2+T1R3) responds to natural sugars, D-amino acids, sweet proteins, and artificial sweeteners. Saccharin, aspartame, acesulfame-K, and cyclamate activate TRPV1 in HEK 293 cell and dissociated primary sensory neurons, and sensitize TRPV1 channels to acid and heat in both systems. These results suggest that interaction of artificial sweeteners with TRPV1 may be involved in the off-taste of sweeteners [95].

5.3. TRPV1 and Umami Taste

Mice lacking Gα-gustducin, PLCβ2, IP3R3, and TRPM5 do not show large deficits in responses to umami taste stimuli [96,97,98,99]. These results suggest that glutamate is detected by multiple receptors and transduction pathways [100,101,102,103]. The candidate umami receptors include a variant of brain-expressed mGluR4, a heteromer (TASR1+TAS1R3), and a variant of the type 1 mGluR1 with a truncated NH2-terminal domain (truncated mGluR1).
TRPV1 KO mice elicited CT responses to MSG solutions containing Bz. Wildtype mice and rats elicited CT responses to MSG solutions containing Bz and SB-366791. In the presence of Bz+SB-366791, there is no contribution of Na+ to glutamate CT response [41]. In both wildtype and TRPV1 KO mice, IMP produced the same magnitude of increase in the CT response to glutamate. Thus, glutamate CT responses are TRPV1-independent.

6. Ligands with Dual Effects on Salty and Umami Tastes

Interestingly, some ligands that modulate salt responses also modulate responses to glutamate albeit at different concentration ranges. NGCC produced an effect on the Am-insensitive NaCl CT response between 1 and 5 μM. In contrast, between 10 μM and 40 μM, NGCC increased the CT response to MSG+Bz+SB-366791. Maximal enhancement was observed at 40 μM and increasing NGCC concentration to 60 or 100 μM did not further increase the response (Table 1). Adding 45 μM NGCC to chicken broth containing 60 mM Na+ enhanced the human umami taste intensity [55]. Although NGCC can directly activate hTRPV1, its effects on glutamate responses are TRPV1-independent. Increasing taste cell Ca2+ inhibited the NGCC-induced increase in CT response to glutamate but not the IMP-induced increase in glutamate response. This suggests that NGCC enhances umami taste by interacting with a Ca2+-dependent transduction pathway [55].
Xyl-MRP modulated Am-insensitive NaCl CT response between 0.1% and 0.5%. In contrast, Xyl-MRP at 2.5% or IMP significantly increased the CT response to MSG+SB366791+Bz (Table 1) [66]. Thus, the responses to glutamate and its enhancement in the presence of IMP and MRPs are indifferent to TRPV1 modulators.
Between 0.1 and 1.0%, FIIm produced a biphasic effect on NaCl+Bz CT responses. At 2.5%, FIIm enhanced the glutamate CT response equivalent to the enhancement with 1 mM IMP (Table 1). In human subjects, 0.3% FIIm produced enhancement of umami taste. These results suggest that FIIm modulates Am-insensitive salt taste and umami taste at different concentration ranges in rats and humans [64].
In HEK293T cells expressing hTRPV1, glutathione and γ-Glu-Val-Gly induced concentration-dependent responses similar to that of Cap. These responses were markedly attenuated by capsazepine, indicating that hTRPV1 may also be the target of kokumi taste stimuli (unpublished observations). Trigeminal ganglion cells co-express TRPV1 (sensitive to Cap) and TRPA1 (sensitive to allyl isothiocyanate). Intracellular Ca2+ imaging showed that pretreatment with γ-Glu-Val-Gly excited 7% of TG cells and increased the amplitude of their responses to allyl isothiocyanate, but not to Cap or menthol. The enhancing effect of γ-Glu-Val-Gly was prevented by a CaSR inhibitor. These results suggest that in cells expressing CaSR, TRPA1, and TRPV1, γ-Glu-Val-Gly preferentially activates TRPA1 [104].

7. Potential Binding Sites of Ligands to Taste Receptors Using In Silico Studies

Two kokumi peptides within yeast extract, IQGFK and EDFFVR, were shown to bind CaSR. IQGFK primarily interacted through electrostatic interactions, with key binding sites including Asp275, Asn102, Pro274, Trp70, Tyr218, and Ser147. EDFFVR mainly engaged via van der Waals energy and polar solvation free energy, with key binding sites being Asp275, Ile416, Pro274, Arg66, Ala298, and Tyr218 [105]. Gamma-glutamyl tripeptides (γ-Glu-Asn-Phe, γ-Glu-Leu-Val, γ-Glu-Leu-Tyr, γ-Glu-Gly-Leu, γ-Glu-Gly-Phe, γ-Glu-Gly-Tyr, γ-Glu-Val-Val, and γ-Glu-Gln-Tyr) induce kokumi taste by entering the Venus flytrap (VFT) of CaSRs and interacting with Ser147, Ala168, and Ser170. These peptides can enhance the umaminess of MSG as they can enter the binding pocket of the taste receptor type 1 subunit 3 (TAS1R3)–MSG complex [106]. Using a novel hypothetical receptor, taste type 1 receptor 3 (TAS1R3)–MSG complex constructed, kokumi-active γ-glutamyl peptides, four amino acid residues, Glu-301, Ala-302, Thr-305, and Ser-306 were critical in ligand–receptor interactions. These results demonstrated that kokumi-active γ-glutamyl peptides enhance the umami taste of MSG, and exhibit synergistic effects by activating TAS1R3 [107].

8. Summary

Acid responses are mediated via OTOP1 expressed in type III TRCs. TRPV1 is involved in responses to acids in the posterior oral cavity and larynx. The TRPV1 trigeminal system and the taste system work in concert to evoke aversive responses to acidic stimuli.
In HBO cells, while high salt increased δ-ENaC protein expression and decreased TRPV1 mRNA expression, Cap decreased δ-ENaC protein expression and increased TRPV1 mRNA expression. This suggests that, in HBO cells, TRPV1 regulates ENaC expression.
A variety of compounds of varying structures (Table 1) produce biphasic taste responses to NaCl in rodents and human subjects that are TRPV1-dependent.
The above compounds also produce biphasic response in CT response to KCl, NH4Cl, and CaCl2 that are also voltage-sensitive. This suggests the presence of a non-selective conductive pathway permeable to Na+, K+, NH4+, and Ca2+ in the anterior tongue.
OTOP1 also detects NH4Cl. Behavioral aversion to NH4Cl was completely abolished in mice that lacked both Type II cells and the OTOP1 channel in Type III cells. These results suggest that the aversive response to NH4Cl is not dependent upon the TRPV1 trigeminal system and resides entirely in Type II and Type III cells.
For the most part, neural and behavioral responses to sweet and umami taste stimuli are not affected by TRPV1 modulators. Artificial sweeteners also activate TRPV1. These results suggest that interaction of artificial sweeteners with TRPV1 may account for the off taste of sweeteners.
While most bitter tastants, including quinine, are transduced by the TAS2R-TRPM5-dependent transduction pathway, nicotine and ethanol are transduced by both a TAS2R-TRPM5-dependent and a TAS2R-TRPM5-independent pathway. The TAS2R-TRPM5-independent pathway is sensitive to nicotinic acetylcholine receptor antagonists. Both nicotine and ethanol activate TRPV1 trigeminal neurons. While aversive responses to ethanol are dependent upon the trigeminal system, the aversive responses to nicotine are not.

9. Future Directions

Future studies should focus on identifying non-selective cation conductance(s) in bitter, sour, and sweet cells that give rise to biphasic taste responses to NaCl, KCl, NH4Cl, and CaCl2 in the presence of TRPV1 modulators. Studies should be pursued to determine if TRPV1 modulators interact with OTOP1 or other acid detection pathways in circumvallate or foliate taste bud cells. It is important to further investigate TRPV1-dependent ENaC regulation in human salt-sensing taste cells by TRPV1 modulators, such as high salt and Cap. It is also imperative to examine the cellular mechanism by which some of the novel peptides described above elicit salt taste by themselves in the absence of Na+.

Funding

This work was supported by VCU Clinical and Translational Research and Value and Efficiency Teaching and Research grants to VL, National Research Foundation of Korea (NRF) grants 2020R1A2C2004661 to MR, and internal funding from Monell Chemical Senses Center to MHO.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Amamiloride
Bzbenzamil
CALHM1Ca2+ homeostasis modulator 1
CALHM3Ca2+ homeostasis modulator 3
CapCapsaicin
CaSRcalcium-sensing receptor
CTChorda tympani taste nerve
CZPCapsazepine
ENaCepithelial Na+ channel
GalAgalacturonic acid, glucosamine
GLglossopharyngeal nerve
GNAT3guanine nucleotide-binding protein G(t) subunit alpha-3
HC-0300312-(1,3-dimethyl-2,6-dioxopurin-7-yl)-N-(4-propan-2-ylphenyl)acetamide
HBO cellscultured adult human fungiform taste cells
HEKhuman embryonic kidney cells
IMPinosine 5′ monophosphate
IP3R3inositol triphosphate receptor type 3
I-RTXiodo–resiniferatoxin
KOknockout
mGluR4metabotropic glutamate receptor 4
MRPsMaillard-reacted peptides
MSGmonosodium glutamate
nAChRnicotinic acetylcholine receptor
NGCCN-geranyl cyclopropyl-carboxamide
NPS R568N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine
NPS-21432-chloro-6-[(2R)-2-hydroxy-3-[(2-methyl-1-naphthalen-2-ylpropan-2-yl)amino]propoxy]benzonitrile;hydrochloride
OTOP1Otopetrin-1
pHiintracellular pH
PIP2phosphatidylinositol 4,5-bisphosphate
PLCβ2phospholipase Cβ2
PKAcAMP-dependent protein kinase A
PKD2L1polycystin-2-like 1 channel
PKD1L3Polycystin-1-like 3, transient receptor potential channel
RAASrenin–angiotensin–aldosterone system
RTXresiniferatoxin
SB-366791N-(3-methoxyphenyl)-4-chlorocinnamide
SLsuperior laryngeal nerve
TAS1R1,
TAS1R2,
TAS1R3		taste type 1 receptors
TAS2Rstaste type 2 receptors
TRCstaste receptor cells
TRPM5Transient Receptor Potential Cation Channel Subfamily M Member 5
TRPM4Transient Receptor Potential Cation Channel Subfamily M Member 4
TRPV1transient receptor potential vanilloid type 1
TRPA1transient receptor potential ankyrin 1
Xylxylose

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Nutrients 16 03858 g001
Figure 1. A proposed mechanism for TRPV1-dependent regulation of ENaC expression in HBO cells. High salt inhibits TRPV1 and Cap activates TRPV1, resulting in changes in [Ca2+]i. Downstream from [Ca2+]i, several intracellular effectors are most likely inhibited or activated that alter ENaC expression [32].
Figure 1. A proposed mechanism for TRPV1-dependent regulation of ENaC expression in HBO cells. High salt inhibits TRPV1 and Cap activates TRPV1, resulting in changes in [Ca2+]i. Downstream from [Ca2+]i, several intracellular effectors are most likely inhibited or activated that alter ENaC expression [32].
Nutrients 16 03858 g001
Table 1. Effect of TRPV1 modulators on Am-insensitive NaCl CT response and Glutamate CT response.
Table 1. Effect of TRPV1 modulators on Am-insensitive NaCl CT response and Glutamate CT response.
TRPV1 ModulatorNaCl CT Response
(Max Increase)		NaCl CT Response
(Max Inhibition)		Glutamate CT Response
Max Increase
Cetylpyridinium chloride250 μM2 mM
CAP 40 μM200 μM
RTX 1 μM10 μM
NGCC2.5 μM50 μM40 μM–100 μM
Nicotine0.015 M0.05 M
Ethanol40%60%
GalA-MRP0.30%1.0%§ 2.5%
Kokumi peptides (FIIm)0.5%1.0%2.5%
Temperature42 °C55 °C
pHo + RTX610
Am-insensitive rat CT responses were recorded by stimulating the tongue with 100 mM NaCl+5 μM Bz in the presence of varying concentrations of TRPV1 modulators. Glutamate rat CT responses were recorded by stimulating the tongue with 100 mM MSG+5 μM Bz+1 μM SB-366791 in the presence of varying concentrations of TRPV1 modulators. § 2.5% Xyl-MRP.
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Rhyu, M.-R.; Ozdener, M.H.; Lyall, V. Differential Effect of TRPV1 Modulators on Neural and Behavioral Responses to Taste Stimuli. Nutrients 2024, 16, 3858. https://doi.org/10.3390/nu16223858

AMA Style

Rhyu M-R, Ozdener MH, Lyall V. Differential Effect of TRPV1 Modulators on Neural and Behavioral Responses to Taste Stimuli. Nutrients. 2024; 16(22):3858. https://doi.org/10.3390/nu16223858

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Rhyu, Mee-Ra, Mehmet Hakan Ozdener, and Vijay Lyall. 2024. "Differential Effect of TRPV1 Modulators on Neural and Behavioral Responses to Taste Stimuli" Nutrients 16, no. 22: 3858. https://doi.org/10.3390/nu16223858

APA Style

Rhyu, M. -R., Ozdener, M. H., & Lyall, V. (2024). Differential Effect of TRPV1 Modulators on Neural and Behavioral Responses to Taste Stimuli. Nutrients, 16(22), 3858. https://doi.org/10.3390/nu16223858

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