Direct activation of Drosophila “sweet” GRNs leads to appetitive feeding behaviors whereas “bitter” GRN activation produces avoidance (15, 19, 43), consistent with mammalian studies on these canonical tastes (1, 44, 45). Drosophila sugar receptors formed from 9 GR genes (sugar GRs) (46–51) detect mono- and disaccharides along with artificial sweeteners and molecules perceived as sweet to humans (52–54). The remaining 30+ GR genes form receptors in “bitter” GRNs (bitter GRs), detecting a range of bitter compounds (e.g., caffeine, lobeline, denatonium, and quinine) (55–58). Recent work in Drosophila has identified two non-canonical bitter signaling pathways for the detection of specific ligands, using rhodopsins and a peptidoglycan recognition protein (PGRP), that open new avenues for taste transduction (Table 1; Figure 1B). Rhodopsin GPCRs are typically light-sensitive with an opsin protein and retinal chromophore, but three rhodopsins (Rh1, Rh4, and Rh7) were found to function as taste receptors that do not require light or retinal (59). These rhodopsins detect aristolochic acid and activate “bitter” GRNs at particularly low concentrations through a phospholipase C (PLC) signaling cascade that involves TRPA1 (59). Mouse taste buds express some opsin RNA (75), suggesting these channels may have a conserved role in chemosensation. The other non-canonical pathway involves PGRPs, pattern recognition receptors traditionally involved in the immune response to pathogens. TRPA1 and canonical bitter GRs (Gr33a, Gr66a) were previously implicated in the detection of bacterial components (76, 77), but the newly described PGRP (PGRP-LB) expressed in the labellum specifically detects bacterial peptidoglycans. Unexpectedly, this receptor uses nuclear factor-κB (NF-κB)/immune deficiency (IMD)-dependent signaling to activate “bitter” GRNs (60). An interest in the role of oral taste receptors in microbial detection has emerged in mammalian research (78, 79), and this recent work in fruit flies highlights an unexpected role for NF-κB/IMD signaling in taste cells that impacts feeding choices (60).

Recent advances in salt taste have revealed a complex taste transduction system that allows for concentration-dependent salt feeding in both mammals and fruit flies (80). A set of “high salt” or “salty” GRNs in the Drosophila labellum are specifically activated by high concentrations of various salt ions (15, 81, 82). Salt also activates other GRNs (“sweet,” “bitter,” and “IR94e”) while inhibiting “water” GRNs, producing a combinatorial code that can lead to flexible behaviors (15). Salt taste research highlights the role of IRs that use the broadly expressed co-receptors, IR25a and IR76b, plus a narrowly expressed “tuning” IR to form functional receptors that detect specific salt ions (15, 82–84). Canonical salt taste centers around NaCl and occasionally other mono- or divalent ions (80), but recent research has shifted focus to identify the taste mechanisms for other ions.

Metals, including divalent and trivalent salt ions, have complex taste profiles (85–87) that have garnered increasing attention due to their accumulation in soil, crops, and foods from human activities (88, 89). Recent studies established that the human bitter taste receptor TAS2R7 acts as a metal cation receptor for detecting zinc and copper (90), yet this can only be demonstrated in vitro. Fruit flies avoid consuming metals and in vivo quantifications of neuronal activity reveal that metal ions activate taste cells through multiple receptors (Table 1; Figure 1B).

In Drosophila, some metal ions require only bitter GRs (Cu²⁺, Ag⁺) or IRs (Mn²⁺, Ni²⁺, Cd²⁺) for detection, while others require both (Zn²⁺, Co²⁺). Interestingly, cellular responses to iron involve both receptor types or solely IRs depending if it is in the Fe²⁺ or Fe³⁺ form, respectively (61). Cadmium sensitivity requires an IR complex in two types of GRNS: co-receptors (IR25a, IR76b) plus IR7a in “bitter” GRNs and the same co-receptors plus IR47a in “salty” GRNs (63). A recent brief report found an additional “tuning” receptor, IR56b, to be necessary for zinc avoidance (62), however, this receptor complex detects NaCl in “sweet” GRNs for attraction (83), so this is an unexpected result. Overall, this research in flies provides clear evidence that a range of individual metal ions have specific taste detection mechanisms. As metal contamination continues to rise, understanding gustatory pathways for metal ligands will become increasingly important across animals with relevance to environmental health and food safety.

pH is an important indicator of food quality and sour taste describes the gustatory detection of acids. Recently, the Otop1 proton channel was identified as the “sour receptor” in mammals (91, 92), and a homolog, OtopLa, is expressed in fruit fly GRNs in the labellum (93, 94). While the discovery of Otop channels was an important breakthrough for sour taste, different acids have distinct taste qualities even at the same pH, suggesting there is more to sour taste than pH alone (95, 96).

Like humans, fruit flies show dose-dependent attraction or aversion to certain carboxylic acids (67). Weak organic acids, such as acetic acid, may have the ability to cross the membrane of taste cells to impact transduction by altering intracellular pH, but through unknown mechanisms (97, 98). In Drosophila, attractive concentrations of specific organic acids—acetic, lactic, glycolic, and citric—require taste receptors for the activation of “sweet” GRNs (64–66). At least one broadly expressed co-receptor, IR25a, is involved, along with sugar GRs for detecting organic acids (64–66) (Table 1; Figure 1B). Even at the same pH, these acids differentially activate Drosophila taste cells in vivo, indicating diverse receptor binding and/or abilities to cross cell membranes. Attempts to distinguish between the detection of pH and anion species show that IRs are largely involved with anion detection, whereas the sugar GRs are responsive to the change in pH (66). Ascorbic acid (Vitamin C), a distinct but related acidic compound, was also found to activate “sweet” GRNs through similar mechanisms (65). High concentrations of carboxylic acids are aversive (99), and IR7a in “bitter” GRNs is specifically required for acetic acid avoidance, without the need for IR co-receptors (67). While the cooperative role of OtopLa channels along with these receptors remains unclear, these findings underscore the dual activation of taste cells by acids through both receptors and proton influx.

Since pH influences food quality, the ability to detect both basic and acidic pH levels would be advantageous. Previous mammalian studies on basic pH sensation focused on somatosensation (100), but humans show alkaline sensitivity on the tip of the tongue (101) and a recent study in rats found that sodium carbonate (Na₂CO₃) solutions activate taste nerves significantly more than Na⁺ alone. However, alkaline taste has not been well described. A recent study in Drosophila established the existence of alkaline taste, and identified a novel receptor required for the detection of basic solutions (70) (Table 1; Figure 1B). Alkaliphile (Alka) is a Cl⁻ channel gated by high pH that is necessary for alkaline taste (70). The Alka receptor is expressed in a subset of the “bitter” GRNs (~21%), but it is currently unclear what other cell types may express this receptor. Regardless, this study in flies establishes a novel tastant-receptor interaction for alkaline taste that may be relevant to mammals. Interestingly, the Otop1 proton channel for sour taste was recently found to be a candidate alkaline receptor in vitro (102), indicating a need for future comparative studies on basic and acidic pH detection mechanisms.

Protein feeding is coupled with the chemical detection of amino acids. Umami taste is a specific savory sensation, usually associated with monosodium L-glutamate (MSG), an amino acid often found in foods at higher concentrations (103–105). The mammalian GPCR complex consisting of T1R1 + T1R3 is referred to as the “umami receptor” (45) and has a high sensitivity to glutamate in humans (106). In most vertebrates, this receptor is broadly responsive to amino acid ligands and amino acids can also activate sugar taste receptors, bitter taste receptors, or act through metabotropic glutamate receptors in multiple cell types (107–114). This combinatorial coding likely occurs in response to individual amino acids in a dose-dependent manner. Through in vitro assays, mammalian bitter receptors display dose-dependent activation by amino acids, however, some inconclusive results are attributed to the possibility of endogenous amino acid receptors in the cell line used for these experiments (109). In vivo studies in Drosophila circumvent these concerns and allow for a deeper understanding of the combinatorial coding for amino acid taste (Table 1).

Fruit flies require and consume amino acids based on internal state, such as mating status or nutritional deficiency (115). The IR co-receptors (IR76b and IR25a) are necessary for detecting most of the proteinogenic amino acids at various concentrations (68, 69, 116), and the “tuning” receptors identified for amino acid sensation to date are IR51b and IR94e. IR51b is a bitter cell-specific receptor that detects high concentrations of arginine, valine, leucine, tryptophan, isoleucine, lysine, and proline (68). IR94e receptors are integral for the detection of glutamate in various forms, and this “tuning” receptor is expressed in a newly described set of taste cells that induce mild feeding aversion (27, 69). A thorough description of the combinatorial coding for low concentrations (25 mM) of arginine reveals that “sweet” GRNs are activated through both sugar GRs (Gr5a, Gr61a, and Gr64f) and IR co-receptors (68) (Figure 1B). The overlap between sugar-sensing and amino acid-sensing resembles a pattern found in mammals (117).

A feature of the mammalian “umami receptor” is enhancement by purine-5′-nucleotides (IMP and GMP) (111, 114, 118), but this feature is not known to occur in fruit flies. Additionally, while no metabotropic glutamate receptors have been identified in fruit fly amino acid taste, the IRs are ancestrally related to ionotropic glutamate receptors (36–38, 119), suggesting a conserved use of glutamate receptors in chemosensation (107, 113, 120). In Drosophila, another intriguing element is that an odorant binding protein (OBP19b) secreted from nearby cells can bind certain amino acids to impact their detection by taste cells (121), but it is unclear how conserved this mechanism may be. Despite some differences from the mammalian system, the Drosophila model offers a way to study dose-dependent encoding of individual or groups of amino acids to better understand this canonical yet complex taste modality.

Fatty acids are highly energetic essential nutrients that are attractive to both mammals and Drosophila (71, 122–124). Initially, fat palatability was thought to be driven by texture and olfaction (125), but more recent research has highlighted the importance of gustation (126–128). In mice, CD36 is a fatty acid transporter expressed in taste buds that contributes to fatty acid preferences (129), and two GPCRs (GPR40 and GPR120) appear to function as lingual fat receptors (130). Although Drosophila homologs have not been discovered, GRNs in the labellum do detect fatty acids (71). Similar to carboxylic and amino acids, the cellular and behavioral responses to fatty acids in flies depend on concentration.

At low concentrations (~0.1%), hexanoic acid elicits appetitive responses in Drosophila, while at high concentrations (~1–2%), it prompts aversion (74). Hexanoic acid attraction is driven by “sweet” GRNs, requiring both IR56d and Gr64d (72–74, 131, 132). Aversion to hexanoic acid is controlled by “bitter” GRNs via three bitter receptors: Gr32a, Gr33a, and Gr66a (74) (Table 1). Recent work has also demonstrated that the fly gustatory system can distinguish between different classes of fatty acids based on chain length (73). While all classes of fatty acids require the IR co-receptors (IR25a and IR76b) for detection, medium-chain fatty acid (MCFA) taste requires “sweet” GRNs and the IR56d receptor, whereas short-chain (SCFA) and long-chain (LCFA) fatty acid taste does not (73). These findings indicate that IR56d is selective for MCFAs, while the co-receptors may function more broadly. However, a recent study questioned the involvement of IR25a and IR76b in the labellar response to the MCFA hexanoic acid (74). The molecular and cellular underpinnings of SCFA/LCFA detection and fatty acid discrimination remain unclear, but these complexities reflect a nuanced fatty acid taste encoding system that is sensitive to both concentration and subtle variations in molecular structure.

MCFA taste also requires intracellular signaling, as flies with a mutant norpA, a Drosophila homolog for PLC, have disrupted MCFA detection (71) (Figure 1B). Whether or not PLC signaling is necessary for SCFA and LCFA sensation is unknown. Furthermore, one study showed that the sugar GR, Gr64e, is an essential component of MCFA signal transduction, unexpectedly serving as a downstream component in the PLC pathway within “sweet” GRNs (133). Notably, a recent investigation found that Gr64e mutation did not affect electrophysiological responses to the MCFA hexanoic acid (74). Despite this discrepancy, activation of a secondary receptor via PLC mimics the mammalian fatty acid signaling cascade. Mice lacking PLC or TRPM5, a downstream receptor in the PLC cascade, lose their taste preference for fatty acids (134). Collectively, these results imply that PLC-mediated intracellular mechanisms underpin fatty acid gustation in both Drosophila and mammals, despite mammalian research primarily focusing on LCFAs which remain attractive at higher concentrations (130). Drosophila fatty acid taste emphasizes the conserved nature of macronutrient taste encoding and may prove valuable for informing future fat perception research to uncover more about this non-canonical taste modality that has many health implications.