*3.2.3 Salt taste receptors*

*Animal Models in Medicine and Biology*

only receptor known to detect fructose [55].

bitter chemicals and "generalists" that detect many [60].

(*Gr*-S) clade [8, 52].

*3.2.2 Bitter receptors*

additional subgroups.

oligosaccharides [8]. The fly sweet receptors belong to the same superfamily of receptors that includes most of the bitter receptors. In adult flies the three key receptors required for sensing sugars, except for fructose, are Gr5a, Gr64a and Gr64f [8, 40, 52–54]. These three receptors are co-expressed in the sugar-responsive GRNs in the labellum, along with five other related GRs that comprise the *Gr*-Sugar

Gr5a and Gr64a sense structurally different sugars. Gr64a participates in the response to sucrose and maltose [8, 52], while Gr5a detect trehalose and melezitose [8, 40, 41]. Gr64f might act as a co-receptor for the responses for all sugars tested except fructose, and functions in concert with Gr5a and Gr64a [53]. Gr43a is the

Bitter taste allows animals to detect toxins in the environment and avoid consuming them. Compounds such as caffeine, cycloheximide (a protein synthesis inhibitor), denatonium (added to rubbing alcohol to discourage consumption), and quinine (a component of tonic water) taste bitter to humans, mice and flies. In vertebrates, bitter chemicals are detected by a small family of receptors (T2Rs), which are structurally related to rhodopsin, and range in number from 3 to 49, depending on the species [31, 34, 56]. In general, each bitter responsive taste receptor cell expresses multiple types of bitter receptors [57], but not all bitter receptors are expressed by every bitter cell [58], leading formally to the possibility that there are subclasses of bitter cells, as is the case in flies [59]. The chemical receptive field of the bitter receptors fall into two classes—"specialists" that detect one or a few

In contrast to vertebrate bitter detection, flies employ a much more complex strategy to sample bitter chemicals. In flies, bitter sensitive GRNs have distinct sensitivities. Based on the response profile to a panel of 16 bitter compounds, the L-, I- and S-type sensilla on the labella are classified into five groups, four of which are sensitive to bitter chemicals (**Figure 1**) [59]. Out of the four, two groups are narrowly tuned to distinct sets of bitter compounds (I-a and I-b). The other two groups respond broadly to bitter tastants but have variable patterns of activity (S-a, S-b). Analysis with a larger panel of bitter compounds may reveal more

In flies, 33 out of 38 *Gr* genes that express in the labellum are found to be localized to bitter GRNs [59]. The roles of only a few of the bitter GRs have been dissected genetically so far. A minimum of 28 *Gr*s can be expressed by some GRNs in the labellum in adult fly. One of the larval GRN classes expresses at least 17 *Gr*s [59, 61]. Many GRs act as co-receptors responding to large numbers of aversive chemicals. *Gr32a*, *Gr33a* and *Gr66a* are needed for detection of most bitter chemicals [62, 63]. These three *Gr*s with additional *Gr*s (*Gr89a* and *Gr39a.a*) are expressed in all bitter responsive GRNs making this group of five GRs to be the "core-bitter GRs" [59]. Other GRs are very narrowly tuned and confer ligand specificity. These receptors are critical in defining the chemical specificity of the GRs, in combination with other GRs. Different combinations of complex sets of GR receptors may explain how a limited number of bitter GRs confer the capacity to respond to a vast collection of structurally diverse bitter compounds. Three TRP channels expressed in the labellum GRNs also contribute to the sensation of aversive compounds through mechanisms that are independent of GRs. TRPA1 show behavioral avoidance to aristolochic acid [64], a related TRPA channel Painless, is required for the behavioral avoidance to isothiocyanates (AITC;

**134**

Moderate levels of salt is necessary to maintain the important physiological functions such as muscle contraction, action potentials and many other functions while excessive salt intake is deleterious and can lead to hypertension. Salty taste is elicited by Na+ concentrations ranging from 10 to 500 mM. In humans, salt taste is amiloride-insensitive. The amiloride sensitive component of salt taste is selective for Na+ and Li+ over other monovalent cations such as K+ , is sensitive to low concentrations of salts (<100 mM), and is generally appetitive [67]. Amiloride-sensitive salt taste occurs only in the front of the tongue [68]. Based on taste nerve recordings, there is a population of broadly tuned high-salt fibers that are insensitive to amiloride and activated by KCl and NaCl [69]. These fibers innervate both the front and back of the tongue, in contrast to the amiloride-sensitive fibers that innervate only the front of the tongue. Epithelial Na+ channels (ENaCs) are composed of three subunits—α, β and γ and α subunit is absolutely essential and forms part of the pore [70]. ENaC α has been suggested to be a component of the low salt sensor since a taste-cell specific knockout eliminates sensitivity and behavioral attraction to low concentrations of salt [71].

The cells that mediate the behavioral responses to high salts are not specifically dedicated to sensing high salt, but instead comprise at least two populations of cells with previously identified functions in sensing bitter and sour [72]. Inactivation of TRPM5 or PLCβ2, expressed by bitter cells, eliminates a component of the high salt response, while silencing PKD2L1-expressing sour cells eliminates the remaining components [72]. Remarkably, mice in which PKD2L1-expressing cells are silenced and TRPM5 is inactivated find high salt concentrations attractive, presumably due to activation of the amiloride-sensitive ENaC channels by high salt [72].

Salt taste preferences in *Drosophila* are similar to those in mammals. Both larvae and adult fruit flies prefer low-salt foods, while they reject high-salt concentrations. Two ENaC channels family members, *ppk11* and *ppk19* are reported to be expressed in the terminal organ and required for sensing low salt [73] in *Drosophila* larvae. However, these channels do not appear to function in the salt response in adults [74]. A member of the ionotropic glutamate receptor (IR) family member, Ir76b, is required for low salt sensing in adult flies [74]. IRs were identified originally as a new class of olfactory receptor [75]. However, several IRs are also expressed in GRNs [76]. Ir76b is expressed in GRNs distinct from those that respond to sugars and bitter compounds, and the Ir76b GRNs extend their projections into a unique region of the SEZ [74]. Most recently combined activity of most of all GRN classes encoding salt taste has been proposed [77].
