Transient Receptor Potential (TRP) Channels and Taste Sensation

Abstract

Humans have 5 basic taste sensations: sweet, bitter, sour, salty, and umami (taste of 1-amino acids). Among 33 genes related to transient receptor potential (TRP) channels, 3—including TRP-melastatin 5 (TRPM5), polycystic kidney disease-1-like 3 (PKD1L3), and polycystic kidney disease-2-like 1 (PKD2L1)—are specifically and abundantly expressed in taste receptor cells. TRP-melastatin 5 is co-expressed with taste receptors T1Rs and T2Rs, and functions as a common downstream component in sweet, bitter, and umami taste signal transduction. In contrast, polycystic kidney disease-1-like 3 and polycystic kidney disease-2-like 1 are co-expressed in distinct subsets of taste receptor cells not expressing TRP-melastatin 5. In the heterologous expression system, cells expressing both polycystic kidney disease-1-like 3 and polycystic kidney disease-2-like 1 responded to sour stimuli, showing a unique “off-response” property. Genetic ablation of polycystic kidney disease-2-like 1-expressing cells resulted in elimination of gustatory nerve response to sour stimuli, indicating that cells expressing polycystic kidney disease-2-like 1 function as sour taste detectors. These results suggest that polycystic kidney disease-1-like 3/polycystic kidney disease-2-like 1 may play a significant role, possibly as taste receptors, in sour taste sensation.

Introduction

Animals make use of their gustatory systems to evaluate the nutritious value, toxicity, sodium content, and acidity of food. Tastants taken into the oral cavity are first detected by taste receptors/channels, which localize at the apical tips of taste cells that form taste buds (Chandrashekar et al., 2006). This information is transmitted to gustatory nerves innervating taste cells, and taste sensation is finally perceived in the brain as sweet, bitter, sour, salty, or umami. There are 4 major taste areas where taste buds are abundantly distributed: the circumvallate papillae, foliate papillae, and fungiform papillae on the tongue, and the palate on the top surface of the mouth. Each taste bud forms an onion-like shape and is composed of 50-100 taste cells. According to staining intensity and ultrastructure in the cytoplasm, observed by electron microscopy, taste cells in each taste bud have been classified into 4 morphological types (Murray, 1973). Different types of taste cells are implicated in distinct functions in taste detection or taste cell development. Type I (dark), type II (light), and type III (intermediate) taste cells are elongated and spindle-shaped, while type IV taste cells are round progenitor cells and are located at the bottom of taste buds. Type II cells do not contain conventional synapses and appear to release ATP as a transmitter in a non-vesicular fashion via pannexin or connexin hemichannels (Finger et al., 2005; Huang et al., 2007; Romanov et al., 2007). In contrast, type III cells form synaptic contacts with the intragemmal nerve fibers and are thought to use serotonin (5-HT) as a neurotransmitter (Fig. 1).

Figure 1.

Signal transduction molecules involved in 5 taste qualities. Sweet, umami, and bitter compounds are detected by 2 distinct families of G-protein-coupled receptors (GPCRs), T1Rs and T2Rs, expressed in type II taste cells. These signals are relayed via the common downstream components, including G-proteins, PLC-b2, IP₃R3. and TRPM5, resulting in ATP release. In contrast, sour compounds are potentially detected by PKD1L3/PKD2L1 heteromers expressed in type III taste cells. Type III cells are supposed to transmit the gustatory information by the neurotransmitter, serotonin.

Among the 5 basic taste sensations (sweet, bitter, sour, salty, and umami), sweet, bitter, and umami compounds are detected by 7 transmembrane G-protein-coupled receptors (GPCRs). Sweet and umami compounds are detected by distinct combinations of T1R family members, consisting of T1R1, T1R2, and T1R3; sweet compounds are detected by T1R2/T1R3 heteromers, while umami compounds are detected by T1R1/T1R3 heteromers (Hoon et al., 1999; Nelson et al., 2001, 2002; Li et al., 2002; Zhao et al., 2003). In contrast, bitter compounds are detected by another family of taste receptors, the T2R family, which consists of approximately 30 members in mammals (Adler et al., 2000; Chandrashekar et al., 2000; Matsunami et al., 2000; Mueller et al., 2005). The T1Rs and the T2Rs are unrelated in sequence, though they both have 7 putative transmembrane domains. A member of a transient receptor potential (TRP) channel, TRPM5, has an essential role in sweet, bitter, and umami taste detection, which will be discussed in detail below.

Many TRP channels play important roles in signal transduction in various sensory systems, including vision, smell, pheromone, hearing, touch, osmolarity, thermosensation, and sweet, bitter, and umami tastes in diverse animal species ranging from mammals and fish to fruit flies and nematodes (Clapham, 2003; Montell, 2005). Some TRP channels function directly as receptors for stimuli by themselves, whereas other TRP channels are downstream effectors of G-protein-coupled sensory receptors. The mammalian TRP family of ion channels consists of 28 members, classified into 6 subfamilies: TRPV, TRPC, TRPM, TRPP, TRPML, and TRPA. Like their founding member, TRP in Drosophila, they have 6 transmembrane domains and a putative pore region. Five PKD1-like family members, not classified as TRP family members, are distantly related to TRP channels in amino acid sequence. Among the TRP family in mammals, TRPV1, initially referred to as vanilloid receptor 1 (VR1), was first identified by an expression cloning method, with capsaicin, the main pungent ingredient of hot chili peppers, as a ligand (Caterina et al., 1997). TRPV1 is also activated by other stimuli, including noxious high temperature and protons as a polymodal channel. The hot and spicy “taste” of capsaicin is a thermal and/or pain sensation, not considered to be a taste quality. Similarly, other members of TRP channels, including TRPA1 activated by pungent ingredients of wasabi and TRPM8 activated by cool-inducing menthol, can also influence one’s eating experience through somatosensory pathways.

In contrast to sweet, bitter, and umami sensations, mechanisms of sensing sour or salty stimuli remain to be elucidated. In electrophysiological analyses of gustatory nerves, 2 pharmacologically distinct components of responses, amiloride-sensitive and amiloride-insensitive, were observed upon stimulation with NaCl, suggesting at least 2 different mechanisms for the detection of salty tastants. Epithelial Na⁺ channels (ENaCs) have been proposed as amiloride-sensitive salty receptors (Kretz et al., 1999). Future genetic studies linking ENaCs and salty taste detection will help establish the role of ENaCs as salty taste receptors. Furthermore, TRPV1 is proposed to have a role in salty taste detection (see below).

Several candidate receptors for sour stimuli have been proposed, including: acid-sensing ion channel-2 (ASIC2) (Ugawa et al., 1998, 2003); HCN1 and HCN4, members of hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) (Stevens et al., 2001); and 2 pore domain K⁺ channels (Lin et al., 2004; Richter et al., 2004). In addition, PKD1L3/PKD2L1 has been recently proposed as the candidate receptor for sour stimuli (Huang et al., 2006; Ishimaru et al., 2006), which will be discussed in detail below. At present, none of these candidate receptors has been demonstrated to be required for sour taste detection in vivo.

TRP-Melastatin 5 (TRPM5)

TRP-melastatin 5 (TRPM5) is a member of the TRPM subfamily consisting of 8 members, TRPM1 to TRPM8 (Liman, 2007). TRPM5 is predicted to assemble as tetramers, similar to other TRP channels. TRPM5 contains 4 TRPM homology regions (MHRs) in the intracellular N-terminal region, and a TRP-motif and a putative coiled-coil domain in the intracellular C-terminal region (Fig. 2). TRPM5 was first reported to be specifically expressed in taste receptor cells (Perez et al., 2002). TRPM5, as well as phospholipase C-β2 (PLC-β2) and inositol 1, 4, 5-triphosphate receptor type 3 (IP₃R3), are co-expressed with either of 2 families of taste receptors, T1Rs or T2Rs (Clapp et al., 2001; Miyoshi et al., 2001; Perez et al., 2002), and function as the common downstream signal transduction components of both T1R and T2R families (Zhang et al., 2003; Damak et al., 2006; Hisatsune et al., 2007). All of the components involved in the taste signal transduction pathways for sweet, bitter, and umami—including T1Rs, T2Rs, alpha-gustducin (a taste-specific G-protein alpha subunit), PLC-β2, and TRPM5—are expressed in restricted types of tissues (McLaughlin et al., 1992; Rossler et al., 1998; Hoon et al., 1999; Yang et al., 2000; Perez et al., 2002). For example, T1Rs and T2Rs are specifically expressed in taste tissues, testis, and small intestine (Hoon et al., 1999; Bezencon et al., 2007). In taste tissues, these molecules are expressed in type II cells (Clapp et al., 2001; Miyoshi et al., 2001; Perez et al., 2002).

Figure 2.

Schematic drawing illustrating conformational structures of TRPM5, PKD1L3, and PKD2L1. TRPM5 is predicted to have 6 transmembrane domains and to assemble as tetramers, containing 4 MHRs in the intracellular N-terminal region, and a TRP-motif and a putative coiled-coil domain in the intracellular C-terminal region. Mouse PKD1L3 is predicted to have 11 transmembrane domains, and contains an N-terminal CLD, 29 S/P-rich repeats, a GPS, and a PLAT/LH2 domain. Note that human PKD1L3 does not contain S/P-rich repeats, even in its genomic sequences. PKD2L1 is predicted to have 6 transmembrane domains and contains a putative Ca²⁺ binding EF hand motif and predicted coiled-coil domain in its C-terminal cytoplasmic tail. MHR, TRPM homology region; CLD, C-type lectin domain; S/P-rich repeats, serine/proline-rich repeats; GPS, G-protein-coupled receptor proteolytic site; PLAT, polycystin-1-lipoxygenase-alpha toxin; LH2, lipoxygenase homology 2; ER, endoplasmic recticulum retention signal; EF hand, calcium-binding domain. Portions of this Figure were modified from Fig.1 in Delmas et al. (2004).

TRPM5 could be gated by the activation of phospholipase C signal transduction pathways downstream of T1R/T2Rs, since intracellular Ca²⁺ opens the channel in heterologous expression systems (Hofmann et al., 2003; Liu and Liman, 2003; Prawitt et al., 2003). Both gustducin and Gαi2 are co-expressed with T1Rs and T2Rs. T2Rs are also shown to couple with gustducin upon ligand stimulation. Gustducin gene knockout mice show diminished response to bitter and sweet chemicals, suggesting its central role in bitter and sweet transduction. Based on these and other results, a model for taste signal transduction for sweet, bitter, and umami taste detection has been proposed (Fig. 1). Sweet, bitter, and umami tastants bind T1Rs or T2Rs, which leads to dissociation of the heterotrimeric G-protein, including alpha-gustducin, Gαi2, Gβ3, and Gγ13. Dissociated β/γ subunits of G-protein activate PLC-β2, which then hydrolyzes phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P₂] into diacylglycerol (DAG) and inositol triphosphate (IP₃). Binding of generated IP₃ to IP₃R3 causes release of Ca²⁺ from intracellular Ca²⁺ stores, which activates TRPM5 channels, generating Na⁺ influx. However, the mechanisms underlying how TRPM5 is actually activated by intracellular Ca²⁺ in taste cells, what happens after the influx of Na⁺ caused by TRPM5 activation, and how taste cells are finally depolarized remain to be elucidated.

Generation and phenotypic analyses of TRPM5 null mice have been reported by two groups (Zhang et al., 2003; Damak et al., 2006). Zhang and colleagues reported that TRPM5 null mice showed complete loss of response to sweet, bitter, and umami stimuli in both behavioral analyses and electrophysiological taste nerve recordings. However, Damak and colleagues reported that TRPM5 null mice showed reduced response to sweet, bitter, and umami stimuli, but that residual responses were observed. These discrepancies between the two studies of TRPM5 gene-targeted mice could be partly due to differences in the construct of targeting vectors. Zhang and colleagues generated mice with a partial deletion of TRPM5, in which exons 15 to 19, encoding 5 of 6 transmembrane domains and the channel pore region, were deleted, but the upstream promoter region and exons 1 to 14, encoding most of the amino terminal region of the gene, remained intact. In contrast, Damak and colleagues generated mice with a partial deletion of TRPM5, in which the first 4 exons and the putative promoter region were deleted, but other regions were retained. The TRPM5 knockout generated by Damak et al. might not represent complete loss-of-function. Alternatively, the knockout generated by Zhang et al. could produce a dominant-negative form of a partial molecule, potentially enhancing the mutants’ phenotype. Other possibilities, including differences in genetic background and detailed experimental conditions, cannot be ruled out.

Interestingly, warm temperature accelerates the activation of TRPM5 (Talavera et al., 2005), providing an explanation for why heating or cooling the tongue can modulate taste sensation. In our experience, cold ice cream ‘feels’ less sweet than warm tea containing the same amount of sugar. Indeed, electrophysiological recordings from mice show that sweet taste is sensitive to temperature, although bitter and umami tastes are not affected (Talavera et al., 2005). There could be other factors that contribute to thermal sensitivity in sweet sensation, since TRPM5 is commonly located as the downstream component of the sweet, bitter, and umami taste receptors, T1Rs and T2Rs.

In summary, TRPM5 functions as a common downstream molecule of sweet, bitter, and umami taste receptors, T1Rs and T2Rs. However, it remains to be elucidated how TRPM5 is activated by intracellular Ca²⁺, and what happens after the influx of Na⁺ caused by TRPM5 activation (Fig. 1).

TRPV1

Salty taste has both amiloride-sensitive and amiloride-insensitive components. TRPV1t, a variant of TRPV1, has been proposed as a candidate amiloride-insensitive salty taste receptor (Lyall et al., 2004). TRPV1 knockout mice showed diminished gustatory nerve responses in the amiloride-insensitive part of salty taste detection. Demonstrating specific expression of TRPV1t in taste cells will greatly help establish the role of TRPV1t in salty taste detection.

Polycystic Kidney Disease-1-Like 3 (PKD1L3) And Polycystic Kidney Disease-2-Like 1 (PKD2L1)

Polycystins consist of polycystic kidney disease-1 (PKD1) and polycystic kidney disease-2 (PKD2), whose mutations cause autosomal-dominant polycystic kidney disease (ADPKD) (Delmas et al., 2004; Nauli and Zhou, 2004). ADPKD is one of the most common inherited diseases, affecting over 1 in 1000 of the world’s population. Characteristics of ADPKD are the progressive development of fluid-filled cysts from the tubules and collecting ducts of affected kidneys. PKD1/PKD2 themselves are thought to function as receptors to sense mechanical flow, osmolarity, and/or unknown extracellular ligand(s) (Nauli et al., 2003). PKD1 is a large protein with a very long N-terminal extracellular domain, followed by 11 transmembrane domains. Due to structural differences, PKD1 and PKD1-like family members are not included in the TRP channel family, although PKD1 shows limited sequence similarity to TRP channels (Ramsey et al., 2006). In contrast, PKD2, which belongs to the TRPP subfamily, has 6 transmembrane domains, similar to other TRP members, and functions as a non-selective cation channel (Gonzalez-Perrett et al., 2001). Association of PKD1 and PKD2 as a heteromer appears to be required for formation of a functional receptor/channel (Hanaoka et al., 2000). There are 4 additional PKD1-like and 2 additional PKD2-like genes found in the mouse or human genome (Nomura et al., 1998; Wu et al., 1998; Chen et al., 1999; Hughes et al., 1999; Guo et al., 2000; Yuasa et al., 2002; li et al., 2003), although their biological functions remain poorly understood.

Polycystic kidney disease-1-like 3 (PKD1L3) is a member of the polycystin-1 (PKD1)-like family consisting of 5 members, including PKD1, PKD1L1, PKD1L2, PKD1L3, and PKDREJ (receptor for egg jelly). PKD1L3, as well as PKD1L2, was first identified from human and mouse genomes as a gene homologous to PKD1 (li et al., 2003). Similar to PKD1, PKD1L3 contains an N-terminal C-type lectin domain, a G-protein-coupled receptor proteolytic site (GPS), and a polycystin-1-lipoxygenase-alpha toxin (PLAT)/lipoxygenase homology 2 (LH2) domain (Fig. 2).

Polycystic kidney disease-2-like 1 (PKD2L1) is a member of the TRPP family consisting of PKD2 (polycystin-2), PKD2L1, and PKD2L2. PKD2L1 was first identified as a gene homologous to PKD2 (Nomura et al., 1998; Wu et al., 1998). Human PKD2L1 shows 50% amino acid sequence identity and 71% similarity with PKD2. PKD2L1 contains a putative Ca²⁺ binding EF hand motif and a predicted coiled-coil domain in its C-terminal cytoplasmic tail (Fig. 2).

RT-PCR and Northern blot analyses showed that PKD1L3 and PKD2L1 are abundantly expressed only in taste tissues and testis (Ishimaru et al., 2006; LopezJimenez et al., 2006), but that PKD2L1 is also expressed in a small subset of brain cells (Huang et al., 2006). In situ hybridization and immunohistochemistry analyses revealed that PKD2L1 is expressed in all the 4 taste areas (Huang et al., 2006; Ishimaru et al., 2006). In contrast, PKD1L3 is expressed in circumvallate and foliate papillae, but not in the fungiform papillae or the palate. In circumvallate and foliate papillae, PKD1L3 and PKD2L1 are co-expressed in the same subset of taste cells, but are distinct from sweet-, bitter-, and umami-sensing cells expressing T1R3, T2Rs, alpha-gustducin, TRPM5, and IP₃R3 (Huang et al., 2006; Ishimaru et al., 2006; LopezJimenez et al., 2006). These results suggest that PKD1L3 and PKD2L1 may be involved in taste qualities other than sweet, bitter, and umami, namely, sour or salty taste. In addition, immunostaining with antibodies generated against PKD2L1 demonstrated that PKD2L1 is localized at the taste pore that contains an accumulation of apical tips of cell dendrites topped with microvilli, suggesting that PKD1L3 and PKD2L1 may function as bona fide taste receptors.

Kataoka and colleagues reported the relationships in expression between PKD2L1 and other marker molecules for type I, type II, or type III taste cells (Kataoka et al., 2008). Immunohistochemistry revealed that PKD2L1-expressing cells show immunoreactivity for markers for type III taste cells such as protein gene-related product 9.5 (PGP-9.5), neural cell adhesion molecule (NCAM), serotonin (5-HT), and the major catecholamine storage vesicle soluble protein, Chromogranin A (CgA) (Nelson and Finger, 1993; Kim and Roper, 1995; Yee et al., 2001; Dvoryanchikov et al., 2007). In contrast, PKD2L1-expressing cells are not immunoreactive for a marker for type I cells, ecto-ATPase (Bartel et al., 2006), or a marker for type II cells, PLC-β2 (Fig. 1).

Diphtheria toxin A fragment (DTA)-mediated ablation of PKD2L1-expressing taste cells clearly showed that these cells are essential for responses to sour stimuli in vivo (Huang et al., 2006). Notably, genetic ablation of the PKD2L1-expressing cells eliminated gustatory nerve responses in the chorda tympani to citric acid, HCl, tartaric acid, and acetic acid. In contrast, these mice, similar to wild-type mice, showed robust nerve responses to sweet, bitter, umami, or salty tastants. These results indicate that PKD2L1-expressing cells function as sour taste sensors.

PKD2L1 is also expressed in a discrete population of neurons surrounding the central canal of the spinal cord, and may function to monitor the pH of the cerebrospinal fluid (Huang et al., 2006). Both sour-sensing cells in taste buds and acid-sensing cells in the central nervous system detect changes in extracellular pH. In both types of cells, intracellular pH also becomes lower as extracellular pH decreases. These results suggest that cells expressing PKD2L1 may play a common role in sensing the extracellular and/or intracellular pH in different cell systems.

Interactions of PKD1L3 and PKD2L1 were examined in human embryonic kidney (HEK) 293T cells transiently expressing PKD1L3 and/or PKD2L1 (Ishimaru et al., 2006). First, a co-immunoprecipitation assay revealed that PKD1L3 and PKD2L1 interact with each other (Ishimaru et al., 2006), as shown in the case of PKD1 and PKD2 (Hanaoka et al., 2000).

Second, both PKD1L3 and PKD2L1 are necessary for forming a functional channel at the cell surface in heterologous cells. When either PKD1L3 or PKD2L1 is solely expressed, it does not localize at the cell surface, but is retained in the intracellular membrane structures. Since PKD1L3 is not expressed in the fungiform papillae or palate, while PKD2L1 is expressed in all the 4 taste regions, it is possible that PKD2L1 has an unidentified partner, other than PKD1L3, in the fungiform papillae or palate.

Finally, the functional property of the PKD1L3/PKD2L1 channel was assessed by Ca²⁺ imaging and patch-clamp analyses with HEK293T cells transiently expressing PKD1L3 and/or PKD2L1 (Ishimaru et al., 2006). In Ca²⁺ imaging experiments, HEK 293T cells transfected with both PKD1L3 and PKD2L1 responded specifically to sour tastants, including citric acid, hydrochloric acid, and malic acid, while they did not respond to sweet, bitter, umami, or salty tastants. In cells expressing PKD1L3 or PKD2L1 alone or control vectors, acid stimuli had little effect, consistent with the idea that PKD1L3 and PKD2L1 heteromer formation is required for their function. In patch-clamp recordings characterizing the electrophysiological properties of PKD1L3- and PKD2L1-mediated currents, the application of a sour tastant caused a robust current with a rapid inactivation. The activation of PKD1L3- and PKD2L1-mediated currents was delayed when compared with the onset of sour stimulation (Ishimaru et al., 2006). Inada and colleagues recently examined the PKD1L3/PKD2L1 channel property in more detail (Inada et al., 2008). They showed that the PKD1L3/PKD2L1 channel responded to various acid solutions adjusted at pH 2.5 or 2.6, including H₂SO₄, phosphoric acid, succinic acid, and tartaric acid, in addition to citric acid, hydrochloric acid, and malic acid. Intriguingly, they demonstrated that the PKD1L3/PKD2L1 channel has a unique “off-response” property, meaning that this channel is gated open only after the removal of an acid stimulus, although initial acid exposure is essential.

What is the physiological significance of the PKD1L3/PKD2L1 channel off-responses? One possibility is that sour taste detection may consist of 2 distinct mechanisms: an on-response and an off-response. Indeed, an off-response as well as an on-response have been reported to be induced by sour stimuli in mammals (DeSimone et al., 1995; Danilova et al., 2002; Lin et al., 2002). In rats, for example, additional off-responses occur in the chorda tympani (CT) nerves and in some acid-responsive taste receptor cells (DeSimone et al., 1995; Lin et al., 2002) following the removal of an acid stimulus. A strong off-response to acidic stimuli has also been detected in both the whole CT and glossopharyngeal nerve, as well as single CT fiber recordings in a New World monkey, the common marmoset (Danilova et al., 2002). The off-response property of the PKD1L3/PKD2L1 channel provides the most feasible explanation for the off-response associated with sour taste perception in mammals. Other unidentified receptors/channels may exist and play a role in an “on-response” induced by sour stimuli. However, it still remains unclear whether off-responses induced by sour stimuli are a universal phenomenon among different species and in different experimental conditions.

Another possibility is that the off-response itself has a major role in sour taste detection in vivo. The taste receptor cells located in the circumvallate and foliate papillae, where PKD1L3 and PKD2L1 are co-expressed, contain salivary glands (von Ebner’s glands) at the bottom of the cleft. Because sour stimuli are known to enhance the immediate secretion of saliva by salivary glands such as the parotid glands (Hodson and Linden, 2006), the acidic solution appears to be instantaneously diluted by saliva in the mouth, resulting in an initial decrease in pH, followed by a quick increase in pH. It is possible that the activation of PKD1L3/PKD2L1 channels may occur shortly after acid stimulation, since a slight increase in pH from the initial acidification at less than pH 3 is sufficient to open the channels (Inada et al., 2008). It remains to be solved whether the off-response of taste cells in vivo is mediated by the PKD1L3/PKD2L1 channel complex, and how the off-response of the channel complex contributes to sour taste sensation.

The genetic ablation of the taste cells expressing PKD2L1 described above seems to ablate sour responses completely. It is possible that our heterologous expression system using HEK293T cells may be lacking additional receptor components that may confer different properties onto the PKD1L3/PKD2L1 channel complex. In the fungiform papillae and palate, PKD2L1 may have an unidentified partner other than PKD1L3, and may have different functions in different taste areas. Notably, other sour taste receptors co-expressed with PKD2L1 might have a major role in sour taste detection. In addition, it is possible that non-taste mechanisms, including somatosensation, may also play significant roles in acid detection, since low pH may cause pain sensation. Generation and analyses of PKD1L3 and PKD2L1 gene knockout mice will help further define the roles of PKD1L3 and PKD2L1 in vivo.

In summary, several lines of evidence suggest that PKD1L3/PKD2L1 is one of the most likely putative sour taste receptors. However, it is still unclear whether the off-response property of PKD1L3/PKD2L1 observed in the heterologous system may reflect phenomena induced by sour stimuli in vivo. Other mechanisms or other candidate taste receptors may also play roles in sour taste transduction (Fig. 3).

Figure 3.

Several models of sour taste detection. (A) When expressed in HEK293T cells, the PKD1L3/PKD2L1 channel showed a unique “off-response” property, meaning that this channel is gated open only after the removal of an acid stimulus, although initial acid exposure is essential. It is possible that our heterologous expression system may be lacking additional receptor components that may confer different properties onto the PKD1L3/PKD2L1 channel complex. (B) Other putative sour taste receptors and mechanisms other than taste buds, including somatosensation, may also play some roles in sour transduction.