taste cell

7/29/2019 taste cell

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The cell biology of taste

Nirupa Chaudhari and Stephen D. Roper

Vol. 190 No. 3, August 9, 2010. Pages 285296.

An incorrect receptor dimer appeared in Fig. 1 of this Review. The corrected Fig. 1 is shown below.

JCB: Correct

Figure 1. Taste qualities, the taste receptors that detect them, and ex-amples of natural stimuli. Five recognized taste qualitiessweet, sour,bitter, salty, and umamiare detected by taste buds. Bitter taste is thought

to protect against ingesting poisons, many of which taste bitter. Sweettaste signals sugars and carbohydrates. Umami taste is elicited by l-aminoacids and nucleotides. Salty taste is generated mainly by Na+ and sourtaste potently by organic acids. Evidence is mounting that fat may alsobe detected by taste buds via dedicated receptors. The names of taste re-ceptors and cartoons depicting their transmembrane topology are shownoutside the perimeter. Bitter is transduced by G proteincoupled receptorssimilar to Class I GPCRs (with short extracellular N termini). In contrast,sweet and umami are detected by dimers of Class III GPCRs (with longN termini that form a globular extracellular ligand-binding domain). One ofthe receptors for Na+ salts is a cation channel composed of three subunits,each with two transmembrane domains. Membrane receptors for sour andfat are as yet uncertain.

Published August 9, 2010


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The Rockeeller University Press $30.00J. Cell Biol. Vol. 190 No. 3 285296

www.jcb.org/cgi/doi/10.1083/jcb.201003144 JCB 28

JCB: Review

Correspondence to Nirupa Chaudhari: [email protected]; orStephen D. Roper: [email protected]

Taste: our most intrepid sense

Sampling the environment through our sense o

taste. Taste is the sensory modaity that guides organisms to

identiy and consume nutrients whie avoiding toxins and in-

digestibe materias. For humans, this means recognizing and dis-

tinguishing sweet, umami, sour, saty, and bitterthe so-caed

basic tastes (Fig. 1). There are ikey additiona quaities such

as atty, metaic, and others that might aso be considered basic

tastes. Each o these is beieved to represent dierent nutritiona

or physioogica requirements or pose potentia dietary hazards.

Thus, sweet-tasting oods signa the presence o carbohydratesthat serve as an energy source. Saty taste governs intake o Na+

and other sats, essentia or maintaining the bodys water ba-

ance and bood circuation. We generay surmise that umami,

the taste o l-gutamate and a ew other l-amino acids, reects

a oods protein content. These stabe amino acids and nuceo-

tide monophosphates are naturay produced by hydroysis

during aging or curing. Bitter taste is innatey aversive and is

thought to guard against consuming poisons, many o which

taste bitter to humans. Sour taste signas the presence o dietary

acids. Because sour taste is generay aversive, we avoid ingest-

ing excess acids and overoading the mechanisms that maintain

acidbase baance or the body. Moreover, spoied oods oten

are acidic and are thus avoided. Nonetheess, peope earn to

toerate and even seek out certain bitter- and sour-tasting com-

pounds such as caeine and citric acid (e.g., in sweet-tart citrus

ruits), overcoming innate taste responses. Variations o taste pre-

erence may arise rom genetic dierences in taste receptors and

may have important consequences or ood seection, nutrition,

and heath (Drayna, 2005; Kim and Drayna, 2005; Dotson et a.,

2008; Shigemura et a., 2009).

An important, i unrecognized aspect o taste is that it serves

unctions in addition to guiding dietary seection. Stimuating

Taste buds are aggregates of 50100 polarized neuro-epithelial cells that detect nutrients and other compounds.Combined analyses of gene expression and cellular func-tion reveal an elegant cellular organization within thetaste bud. This review discusses the functional classes oftaste cells, their cell biology, and current thinking on howtaste information is transmitted to the brain.

Review series

The cell biology oftaste

Nirupa Chaudhari and Stephen D. Roper

Department o Physiology and Biophysics, and Program in Neurosciences, University o Miami Miller School o Medicine, Miami, FL 33136

2010 Chaudhari and Roper This article is distributed under the terms o an AttributionNoncommercialShare AlikeNo Mirror Sites license or the frst six months ater the pub-lication date (see http://www.rupress.org/terms). Ater six months it is available under aCreative Commons License (AttributionNoncommercialShare Alike 3.0 Unported license,as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Figure 1. Taste qualities, the taste receptors that detect them, and ex-amples o natural stimuli. Five recognized taste qualitiessweet, sour,bitter, salty, and umamiare detected by taste buds. Bitter taste is thoughtto protect against ingesting poisons, many o which taste bitter. Sweettaste signals sugars and carbohydrates. Umami taste is elicited by l-aminoacids and nucleotides. Salty taste is generated mainly by Na + and sourtaste potently by organic acids. Evidence is mounting that at may alsobe detected by taste buds via dedicated receptors. The names o taste re-ceptors and cartoons depicting their transmembrane topology are shownoutside the perimeter. Bitter is transduced by G proteincoupled receptorssimilar to Class I GPCRs (with short extracellular N termini). In contrast,sweet and umami are detected by dimers o Class III GPCRs (with longN termini that orm a globular extracellular ligand-binding domain). One othe receptors or Na+ salts is a cation channel composed o three subunits,each with two transmembrane domains. Membrane receptors or sour andat are as yet uncertain.



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28Cells, synapses, and signals in taste buds Chaudhari and Roper

cavity (Fig. 2 A). In humans, there are 5,000 taste buds in the

ora cavity, situated on the superior surace o the tongue, on the

paate, and on the epigottis (Mier, 1995). Taste buds across

the ora cavity serve simiar unctions. Athough there are subte

regiona dierences in sensitivity to dierent compounds over

the ingua surace, the ot-quoted concept o a tongue map

defning distinct zones or sweet, bitter, saty, and sour has argey

been discredited (Lindemann, 1999).

The eongate ces o taste buds are mature dierentiated

ces. Their apica tips directy contact the externa environment

in the ora cavity and thus experience wide uctuations o tonic-

ity and osmoarity, and the presence o potentiay harmu com-

pounds. Hence, taste bud ces, simiar to oactory neurons,

comprise a continuousy renewing popuation, quite unike the

sensory receptors or vision and hearing: photoreceptors and

hair ces. It is now cear that adut taste buds are derived rom

oca epitheium. At east some precursor ces are common be-

tween taste buds and the stratifed nonsensory epitheium sur-

rounding them (Stone et a., 1995; Okubo et a., 2009).

Tight junctions connecting the apica tips o ces were

noted in eectron micrographs o taste buds rom severa species(Murray, 1973, 1993). Typica tight junction components such

as caudins and ZO-1 are detected at the apica junctions

(Michig et a., 2007). Taste buds, ike most epitheia, impede the

permeation o water and many soutes through their interceuar

spaces. Nevertheess, paraceuar pathways through taste buds

have been demonstrated or certain ionic and nonpoar com-

pounds (Ye et a., 1991). Indeed, permeation o Na+ into the in-

terstitia spaces within taste buds may contribute to the detection

o saty taste (Simon, 1992; Rehnberg et a., 1993).

Considering the strongy poarized shapes o taste ces,

reativey ew proteins have been shown to be partitioned

into the apica membrane. Exampes incude aquaporin-5

(Watson et a., 2007) and a K channe, ROMK (Dvoryanchikovet a., 2009).

Eectron micrographs o taste buds revea ces o vary-

ing eectron densities that were interpreted as reecting a con-

tinuum o stages o dierentiation or maturation. However,

precise morphometric anayses (i.e., eectron density o cyto-

pasm, shape o nuceus, ength and thickness o microvii,

and the presence o speciaized chemica synapses) demon-

strated that ces in taste buds were o discrete types (Murray,

1993; Pumpin et a., 1997; Yee et a., 2001). Utrastructura

eatures served as the basis or a recassifcation o taste ces.

Taste buds were described as containing ces imaginativey

termed Types I, II, and III, and Basa, a nonpoarized, presum-

aby undierentiated ce, sometimes termed Type IV. What

was missing was a convincing argument that these morphotypes

represented distinct unctiona casses.Figure 2. Cell types and synapses in the taste bud. (A) Electron micro-graph o a rabbit taste bud showing cells with dark or light cytoplasm, andnerve profles (arrows). Asterisks mark Type II (receptor) cells. Reprintedwith permission rom J. Comp. Neurol. (Royer and Kinnamon, 1991).(B) A taste bud rom a transgenic mouse expressing GFP only in recep-tor (Type II) cells. Presynaptic cells are immunostained (red) or aromaticamino acid decarboxylase (a neurotransmitter-synthesizing enzyme that isa marker or these cells), and are distinct rom receptor cells, identifed byGFP (green). Reprinted with permission rom J. Neurosci. (C) Taste budsimmunostained or NTPDase2 (an ectonucleotidase associated with theplasma membrane o Type I cells) reveal the thin lamellae (red) o Type I cells.These cytoplasmic extensions wrap around other cells in the taste bud.

GFP (green) indicates receptor cells as in B. Bar, 10 m. Image courtesyo M.S. Sinclair and N. Chaudhari. (D) High magnifcation electron micro-graph o a synapse between a presynaptic taste cell and a nerve terminal (N)in a hamster taste bud. The nucleus (Nu) o the presynaptic cell is at the top,and neurotransmitter vesicles cluster near the synapse(s). The nerve pro-fle includes mitochondria (m) and electron-dense postsynaptic densities.mt, microtubule. Image courtesy o J.C. Kinnamon.



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JCB VOLUME 190 NUMBER 3 2010288

Type II (receptor) cells. There is itte ambiguity in

how Type II ces unction within taste buds. Embedded in the

pasma membrane o these ces are receptors that bind sweet,

bitter, or umami compounds. These taste receptors are G protein

couped receptors with seven transmembrane domains. Signaing

events downstream o these receptors are we documented

and are discussed under Transduction beow (or review see

Margoskee, 2002; Bresin and Huang, 2006; Simon et a., 2006).

In addition, Type II ces express votage-gated Na and K chan-

nes essentia or producing action potentias, and hemichanne

subunits, key payers in taste-evoked secretion o ATP (yeow

ce in Fig. 3). Any given Type II ce expresses taste GPCRs spe-

cifc or ony one taste quaity, such as sweet or bitter, but not both

(Neson et a., 2001). Correspondingy, a given receptor ce re-

sponds ony to stimuation with igands that activate those recep-

tors. In brie, Type II ces are tuned to sweet, bitter, or umami

taste (Tomchik et a., 2007). In recognition o their roe as the pri-

mary detectors o these casses o tastants, Type II ces were re-

named receptor ces (DeFazio et a., 2006). Type II ces do not

appear to be directy stimuated by sour or saty stimui.

Curiousy, receptor ces do not orm utrastructuray iden-tifabe synapses. Instead, nerve fbers, presumaby gustatory

aerents, are cosey apposed to these ces (Murray, 1973, 1993;

Yang et a., 2000; Yee et a., 2001; Capp et a., 2004). Signas

transmitted rom receptor ces to sensory aerents or other ces

within the taste bud must do so by unconventiona mechanisms,

i.e., without the invovement o synaptic vesices, as wi be de-

scribed beow.

Type III (presynaptic) cells. The consensus is that

Type III ces (green ce in Fig. 3) express proteins associated

with synapses and that they orm synaptic junctions with nerve

terminas (Murray et a., 1969; Murray, 1973, 1993; Yang et a.,

2000; Yee et a., 2001). These ces express a number o neurona-

ike genes incuding NCAM, a ce surace adhesion moecue,enzymes or the synthesis o at east two neurotransmitters,

and votage-gated Ca channes typicay associated with neuro-

transmitter reease (DeFazio et a., 2006; Dvoryanchikov

et a., 2007). Type III ces, expressing synaptic proteins and

showing depoarization-dependent Ca2+ transients typica o

synapses, have been abeed presynaptic ces (DeFazio et a.,

2006). Like receptor ces, presynaptic ces aso are excitabe

and express a compement o votage-gated Na and K channes

to support action potentias (Meder et a., 2003; Gao et a.,

2009; Vandenbeuch and Kinnamon, 2009a,b). The origin o

nerve fbers that synapse with Type III ces, and whether they

represent taste aerents, is not known. In addition to these neu-

rona properties, presynaptic ces aso respond directy to sour

taste stimui and carbonated soutions and are presumaby the

ces responsibe or signaing these sensations (Huang et a.,

2006; Tomchik et a., 2007; Huang et a., 2008b; Chandrashekar

et a., 2009).

A key eature o presynaptic ces is that they receive input

rom and integrate signas generated by receptor ces (see beow).

Hence, in the intact taste bud, unike receptor ces, presynaptic

ces are not tuned to specifc taste quaities but instead respond

broady to sweet, saty, sour, bitter, and umami compounds

(Tomchik et a., 2007). Athough presynaptic ces share many

Subsequenty, investigators have probed taste buds with

antibodies at both ight and eectron microscopic eves, thus

associating a ew protein markers with the utrastructuray de-

fned ce types. These markers incuded -gustducin (a taste-

seective G subunit invoved in taste transduction) in Type II

ces and SNAP25 (a core component o SNARE compexes

that reguate exocytosis o synaptic vesices) in Type III ces

(Yang et a., 2000; Yee et a., 2001; Capp et a., 2004). Immuno-

staining in pairwise combinations then expanded the numbers

o taste-specifc proteins that coud be assigned excusivey to

ces o Type I, II, or III. Fig. 2 B demonstrates the cear distinc-

tion between ce Types II and III, with ew i any ces exhibit-

ing an intermediate pattern o gene expression. Simiary, ce

Types I and II are separate popuations (Fig. 2 C). Type III ces

are the ony ces that exhibit we-dierentiated synapses

(Fig. 2 D). An important advance has been with the generation

o transgenic mice with GFP expressed rom promoters seec-

tivey active in Type II or III ces. This has aowed a precise

integration between unctiona properties, morphoogica ea-

tures, and gene expression patterns o the ce types within taste

buds. For instance, by combining patch-camp and immuno-staining on tissues rom such mice, Meder et a. (2003) showed

that votage-gated Ca2+ currents, de rigeur components o syn-

apses, are imited to the Type III ces. In contrast, Ca2+ imaging

in combination with transgenic markers demonstrated that

Type II ces respond to sweet, bitter, or umami taste stimui whie

acking votage-gated Ca channes (Capp et a., 2006; DeFazio

et a., 2006).

Type I cells. Type I ces are the most abundant ces in

taste buds, with extended cytopasmic ameae that engu other

ces (Fig. 2 C). Type I ces express GLAST, a transporter or gu-

tamate, indicating that they may be invoved in gutamate uptake

(Lawton et a., 2000). Type I ces aso express NTPDase2, a

pasma membranebound nuceotidase that hydroyzes extrace-uar ATP (Barte et a., 2006). ATP serves as a neurotransmitter in

taste buds (Finger et a., 2005) and gutamate aso is a candidate

neurotransmitter. Thus, Type I ces appear to be invoved in termi-

nating synaptic transmission and restricting the spread o transmit-

ters, a roe perormed in the centra nervous system by gia ces.

Type I ces aso express ROMK, a K channe that may be

invoved in K+ homeostasis within the taste bud (Dvoryanchikov

et a., 2009). During proonged trains o action potentias eic-

ited by intense taste stimuation, Type I ces may serve to eimi-

nate K+ (see bue ce in Fig. 3) that woud accumuate in the

imited interstitia spaces o the taste bud and ead to diminished

excitabiity o Type II and III ces. This is another stereotypic

gia unction. Patch-camp studies have suggested that some

taste ces, presumaby Type I ces, possesses eectrophysioog-

ica properties, such as inexcitabiity and high resting K+ con-

ductance, aso characteristic o gia (Bigiani, 2001). Thus, Type I

ces appear overa to unction as gia in taste buds. A caveat is

that not a Type I ces necessariy participate in each o the gia

roes described above.

Lasty, Type I ces may exhibit ionic currents impicated

in sat taste transduction (Vandenbeuch et a., 2008). Despite

their being the most abundant ce type in taste buds, the east is

known about Type I ces.



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Nerve bers. Taste buds are innervated by sensory

neurons whose ce bodies are ocated in custers nested against

the brain (the genicuate, petrosa, and nodose crania gangia).

In the adut, each taste bud is innervated by 314 sensory gan-

gion neurons, depending on the species (mouse, rat, hamster)

and ora region (tongue, paate; Krimm and Hi, 1998; Whitehead

et a., 1999). Gustatory nerve fbers cominge with a rich pexus o

other nerve fbers under the taste epitheium. In the absence o

cear markers to distinguish them, one cannot discern which

o these fbers carry taste inormation as opposed to pain,

neuron-ike properties, it is cear that they are not a homogeneous

popuation (Tomchik et a., 2007; Roberts et a., 2009).

Basal cells. This category describes spherica or ovoid

ces that do not extend processes into the taste pore and are

ikey to be undierentiated or immature taste ces (Farbman,

1965). It is not cear whether a basa ces within taste buds

represent a common undierentiated cass o ces. Unambigu-

ous markers or these ces have not been identifed, and the

exact signifcance o basa ces as a ce popuation remains to

be eucidated.

Figure 3. The three major classes o taste cells. This classifcation incorporates ultrastructural eatures, patterns o gene expression, and the unctions oeach o Types I, II (receptor), and III (presynaptic) taste cells. Type I cells (blue) degrade or absorb neurotransmitters. They also may clear extracellularK+ that accumulates ater action potentials (shown as bursts) in receptor (yellow) and presynaptic (green) cells. K+ may be extruded through an apical Kchannel such as ROMK. Salty taste may be transduced by some Type I cells, but this remains uncertain. Sweet, bitter, and umami taste compounds activatereceptor cells, inducing them to release ATP through pannexin1 (Panx1) hemichannels. The extracellular ATP excites ATP receptors (P2X, P2Y) on sensorynerve fbers and on taste cells. Presynaptic cells, in turn, release serotonin (5-HT), which inhibits receptor cells. Sour stimuli (and carbonation, not depicted)directly activate presynaptic cells. Only presynaptic cells orm ultrastructurally identifable synapses with nerves. Tables below the cells list some o theproteins that are expressed in a cell typeselective manner.



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occur in distinct subsets o ces within taste buds (Maruyama

et a., 2006) and neura responses show simiary heterogeneous

patterns (Yoshida et a., 2009b), observations that urther sug-

gest that umami taste is compex, and ikey mediated through

mutipe types o taste receptors. In summary, athough the

T1R1+T1R3 dimer ceary acts as an umami receptor, additiona

GPCRs may pay compementary roes. Candidates or addi-

tiona umami receptors incude a taste-specifc variant or other

isoorms o G proteincouped gutamate receptors expressed in

taste buds (Chaudhari et a., 2000; Li et a., 2002; Neson et a.,

2002; San Gabrie et a., 2009).

The T1Rs are dimeric Cass III GPCRs, with arge

N-termina extraceuar domains (Max et a., 2001). This do-

main orms a Venus Fytrap structure as in other amiy mem-

bers. T1Rs aso possess a mutitude o additiona igand-binding

sites on the exterior aces o the ytrap, in the inker, and per-

haps even in the pane o the membrane (Cui et a., 2006;

Temussi, 2009). In contrast, T2Rs resembe Cass I GPCRs with

binding sites in the transmembrane heices, in keeping with the

nonpoar nature o many bitter igands (Foriano et a., 2006).

When they bind taste moecues, taste GPCRs activateheterotrimeric GTP-binding proteins (Fig. 4 A). For exampe,

the bitter receptors (T2Rs) are coexpressed with and activate the

taste-seective G subunit, -gustducin, and the cosey reated

-transducin (Ruiz-Avia et a., 1995). Taste receptors that in-

cude T1R3 may coupe to G14 and other G subunits (Tizzano

et a., 2008). Despite this apparent seectivity o taste GPCRs

or G subunits, the principa pathway or taste transduction

appears to be via G, incuding G13 and G1 or G3 (Huang

et a., 1999). Upon igand binding, the G subunits are reed

rom the taste GPCR and interact unctionay with a phospho-

ipase, PLC2, an unusua isoorm that is activated by G

rather than the more common Gq amiy subunits (Rsser

et a., 1998). Knocking out PLC2 severey diminishes, but doesnot eiminate taste sensitivity (Zhang et a., 2003; Dotson et a.,

2005). PLC2 stimuates the synthesis o IP3, which opens

IP3R3 ion channes on the endopasmic reticuum, reeasing

Ca2+ into the cytoso o receptor ces (Simon et a., 2006; Roper,

2007). The eevated intraceuar Ca2+ appears to have two tar-

gets in the pasma membrane: a taste-seective cation channe,

TRPM5, and a gap junction hemichanne, both ound in recep-

tor ces (Prez et a., 2002; Huang et a., 2007). The Ca 2+-

dependent opening o TRPM5 produces a depoarizing generator

potentia in receptor ces (Liu and Liman, 2003). I sufcienty

arge, generator potentias evoke action potentias in receptor

ces. The two signas eicited by tastants: strong depoarization

and increased cytopasmic Ca2+, are integrated by gap junction

hemichannes. The outcome o this convergence is that the taste

bud transmitter, ATP, and possiby other moecues, are secreted

through the hemichanne pores into the extraceuar space

surrounding the activated receptor ce (Fig. 3, yeow ce; and

Fig. 4 A; Huang et a., 2007; Romanov et a., 2007; Huang

and Roper, 2010).

Athough most researchers agree that ATP reease occurs

through a pasma membrane hemichanne, whether these chan-

nes are ormed o pannexin (Panx) or connexin (Cx) subunits is

not uy resoved. Panx1 is robusty expressed in receptor ces,

tactie, or therma signas. Taste axons branch and penetrate the

basa amina to enter taste buds. Athough some fbers terminate

in synaptic structures on Type III ces, others course intimatey

among taste ces without orming speciaized synapses (Farbman,

1965; Murray et a., 1969; Murray, 1973).

As wi be expained next, the concerted action o Type I,

Type II (receptor), and Type III (presynaptic) ces underies taste

reception. There are synaptic interactions, both eed-orward

and eedback, between these ces when taste stimui activate

the taste bud.

Beyond the tasty morsel: the

underlying molecular mechanisms or

nutrient detection

Transduction o gustatory stimuli in receptor

(Type II) cells. As stated above, sweet, umami, and bitter

compounds each activate dierent taste GPCRs that are ex-

pressed in discrete sets o receptor ces. For instance, receptor

ces that express members o the T2R amiy o GPCRs sense

bitter compounds (Chandrashekar et a., 2000). In dierent

mammas, 2035 separate genes encode members o the T2Ramiy. These taste receptors exhibit heterogeneous moecuar

receptive ranges: some are narrowy tuned to 24 bitter-tasting

compounds, whereas others are promiscuousy activated by nu-

merous igands (Meyerho et a., 2010). On the basis o in situ

hybridizations with mixed probes on rodent taste buds, the T2Rs

were reported either to be expressed as overapping subsets o

mRNAs (Matsunami et a., 2000) or coexpressed in a singe

popuation o taste ces (Ader et a., 2000). More recenty, de-

taied anayses on human taste buds confrm that dierent bitter-

responsive taste ces express subsets o 411 o the T2Rs in

partiay overapping ashion (Behrens et a., 2007). This obser-

vation is important insoar as it provides a moecuar basis or

discriminating between dierent bitter compounds. Bitter-sensingtaste ces are known to unctionay discriminate among bitter

compounds (Caicedo and Roper, 2001). This pattern o T2R ex-

pression, aong with poymorphisms across the gene amiy, is

thought to aow humans and animas to detect the enormous

range o potentiay toxic bitter compounds ound in nature

(Drayna, 2005).

Receptor ces expressing the heterodimer T1R2+T1R3

respond to sugars, synthetic sweeteners, and sweet-tasting pro-

teins such as monein and brazzein (Neson et a., 2001; Jiang

et a., 2004; Xu et a., 2004). Athough the persistence o sensi-

tivity to some sugars in mice acking T1R3 suggests that addi-

tiona receptors or sweet may exist (Damak et a., 2003),

candidate receptors have yet to be identifed.

A third cass o receptor ces expresses the heterodimeric

GPCR, T1R1+T1R3, which responds to umami stimui, particu-

ary the combination o l-gutamate and GMP/IMP, compounds

that accumuate in many oods ater hydroysis o proteins and

NTPs (Li et a., 2002; Neson et a., 2002). Nevertheess, robust

physioogica responses and behaviora preerence or umami

tastants persist in mice in which T1R3 is knocked out, suggest-

ing that additiona taste receptors may contribute to umami de-

tection (Damak et a., 2003; Maruyama et a., 2006; Yasumatsu

et a., 2009). Functiona responses to various umami tastants



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this question, namey testing ATP reease rom taste ces rom

Panx1 or Cx knockout mice, has yet to be reported.

Presynaptic (Type III) cells also detect some

taste stimuli. Presynaptic ces exhibit very dierent taste

sensitivity and transduction mechanisms when compared with

receptor ces. Sour taste stimui (acids) excite presynaptic ces

(Tomchik et a., 2007). The membrane receptor or ion channe

that transduces acid stimui remains as yet unidentifed. Non-

seective cation channes ormed by PKD2L1 and PKD1L3 were

proposed as candidate sour taste receptors (Huang et a., 2006;

Ishimaru et a., 2006; LopezJimenez et a., 2006). Yet, this

channe is sensitive to extraceuar pH rather than a drop in

cytopasmic pH, which is known to be the proximate stimuus

or sour taste (Fig. 4 B; Lya et a., 2001; Huang et a., 2008b).

Further, mice acking PKD1L3 remain capabe o detecting

acid taste stimui (Neson et a., 2010). More ikey candidate

acid receptors in Type III ces are pasma membrane channes

that are moduated by cytopasmic acidifcation, such as certain

K channes (Lin et a., 2004; Richter et a., 2004). Presynaptic

ces aso detect carbonation, party through the action o

carbonic anhydrase that produces protons and thus acidifesthe environment (Graber and Keeher, 1988; Simons et a.,

1999; Chandrashekar et a., 2009). The compete transduc-

tion pathways or carbonation and sour taste have not been

competey described.

Salt detection and transduction. Taste buds de-

tect Na sats by directy permeating Na+ through apica ion

channes and depoarizing taste ces. An ion channe that has

ong been thought to mediate this action is the amioride-sensitive

epitheia Na channe, ENaC (Fig. 4 C; Heck et a., 1984; Lin et a.,

1999; Lindemann, 2001). This notion was recenty confrmed

by knocking out a critica ENaC subunit in taste buds, which

impaired sat taste detection (Chandrashekar et a., 2010). This

study did not assign sat sensitivity to any o the estabishedtaste ce types, but patch-camp studies suggested that Na+-

detecting ces are Type I ces (Vandenbeuch et a., 2008). Pharma-

coogica and other evidence suggests that sat transduction in

human and anima modes aso occurs via additiona membrane

receptors or ion channes. Athough a modifed TrpV1 channe

has been proposed as a candidate Na+ taste transducer, knockout

mice show a minima phenotype with respect to sat detection

(Ruiz et a., 2006; Treesukoso et a., 2007).

Inormation processing and cell-to-cell

signaling in taste buds: teasing apart our

taste response

Transmitters and inormation fow. Receptor and pre-

synaptic ces each reease dierent neurotransmitters (Huang

et a., 2007). To date, receptor ces are known to reease ony

ATP, via pannexin channes as described above. Presynaptic

ces on the other hand, secrete serotonin (5-HT) and nor-

epinephrine (NE). In some instances presynaptic ces co-reease

both these amines (Dvoryanchikov et a., 2007; Huang et a., 2008a).

Secretion o these biogenic amines appears to be via conven-

tiona Ca2+-dependent exocytosis. Custers o monoaminergic

vesices are present at synapses in eectron micrographs o

mouse presynaptic ces (Takeda and Kitao, 1980).

whereas severa Cx subunits are expressed at more modest ev-

es (Huang et a., 2007; Romanov et a., 2007). Athough there

may be gap junctions presumaby ormed o connexins between

ces in mammaian taste buds (Yoshii, 2005), such junctions

woud not be expected to secrete ATP into extraceuar spaces.

A principa argument or Cx hemichannes in taste ces was

based on the bocking action o certain isoorm-seective mi-

metic peptides. However, the specifcity o such peptides has

recenty been caed into question (Wang et a., 2007). Finay,

Panx1 hemichannes are gated open by eevated cytopasmic

Ca2+ and/or membrane depoarization (Locovei et a., 2006).

ATP reease rom taste ces simiary is mediated by both Ca2+

and votage (Huang and Roper, 2010). In contrast, Cx hemi-

channes usuay open ony in the absence o extraceuar Ca2+

and typicay are bocked by eevated cytopasmic Ca2+. Further,

Panx1-seective antagonists bock taste-evoked ATP secretion

(Huang et a., 2007; Dando and Roper, 2009). Thus, the weight o

the evidence strongy avors ATP reease through Panx1 hemi-

channes in receptor ces. Nevertheess, the idea test to resove

Figure 4. Mechanisms by which fve taste qualities are transduced intaste cells. (A) In receptor (Type II) cells, sweet, bitter, and umami ligandsbind taste GPCRs, and activate a phosphoinositide pathway that elevatescytoplasmic Ca2+ and depolarizes the membrane via a cation channel,TrpM5. The combined action o elevated Ca2+ and membrane depolariza-tion opens the large pores o gap junction hemichannels, likely composedo Panx1, resulting in ATP release. Shown here is a dimer o T1R tasteGPCRs (sweet, umami). T2R taste GPCRs (bitter) do not have extensiveextracellular domains and it is not known whether T2Rs orm multimers.(B) In presynaptic (Type III) cells, organic acids (HAc) permeate throughthe plasma membrane and acidiy the cytoplasm where they dissociate toacidiy the cytosol. Intracellular H+ is believed to block a proton-sensitive Kchannel (as yet unidentifed) and depolarize the membrane. Voltage-gatedCa channels would then elevate cytoplasmic Ca2+ to trigger exocytosis o

synaptic vesicles (not depicted). (C) The salty taste o Na+

is detected bydirect permeation o Na+ ions through membrane ion channels, includingENaC, to depolarize the membrane. The cell type underlying salty tastehas not been defnitively identifed.



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The question o coding has been addressed through ge-

netic manipuations and physioogica and behaviora assays.

Eectrophysioogica recordings rom singe aerent fbers or

their parent sensory gangion ces indicated that some neurons

respond strongy to a singe taste quaity (usuay sweet), but

aso have weak responses to other tastes. In contrast, other a-

erent neurons are excited by mutipe tastes, i.e., are broady

responsive (Heekant et a., 1997; Frank et a., 2008; Breza

et a., 2010). Thus, aerent taste neurons show response profes

simiar to both narrowy tuned taste bud receptor ces and to

broady tuned presynaptic ces. The pattern o aerent neuron

activity mirrors the heterogeneity o taste bud ceuar responses

(Gibertson et a., 2001; Caicedo et a., 2002; Tomchik et a.,

2007; Yoshida et a., 2009a; Breza et a., 2010) and suggests that

neura activity encoding taste does not oow a simpe dedi-

cated abeed-ine ogic. That is, bitter-specifc, sour-specifc,

etc., aerent sensory ibers and subsequent neurons in the

networkobigatory components o abeed-ine codinghave

never been reported.

An argument or abeed-ine coding has been made based

on the resuts o repacing a modifed opioid receptor or thebitter or sweet receptors in taste ces (Zhao et a., 2003; Mueer

et a., 2005). Mice engineered with this oreign receptor in

sweet receptor ces strongy preerred and copiousy drank

soutions o a synthetic igand or the modifed receptor, as i

the compound tasted sweet. For norma mice, the igand was

tasteess. Conversey, when the opioid receptor was targeted to

bitter receptor ces, the same igand was strongy aversive.

Athough this was presented as frm proo o abeed-ine cod-

ing, the ogic bears reexamining. Take or exampe a computer

keyboard. Striking the A key activates a combination o eec-

tronic signas that resuts in the iumination o a combination

o pixes to produce the frst etter o the aphabet on screen.

I the pastic key (the receptor) on the keyboard were changed,striking the repacement key woud sti produce the etter A

on screen. The experiment does not inorm one about the eec-

tronic coding that is out o sight between the two visibe events,

and does not impy that abeed wires ink the base o the key to

particuar pixes. Chemosensory researchers agree that abeed

taste ces exist. Labeed ines remain controversia.

In summary, sweet, bitter, and umami ces a secrete the

same neurotransmitter, ATP, onto aerent fbers. Discrete syn-

apses are acking that might coupe receptor ces with sensory

aerent fbers to transmit singe taste quaities. Athough some

taste ces and sensory aerent neurons are tighty tuned, others

are responsive to mutipe taste quaities. Thus, it remains an open

question exacty how inormation gathered by we-dierentiated

receptor ces in taste buds is coded or the eventua perception

o distinct taste quaities.

Future directions in taste research

Taste research, athough making tremendous strides in recent

years, has exposed major gaps in our understanding. Among the

open questions is the moecuar identifcation o additiona taste

receptors. Known taste receptors do not account or a igands

and sensory characteristics or sweet and umami tastes. It is

ikey that there are additiona, undiscovered sweet and umami

Gustatory stimui initiate a sequence o chemica signas

that are passed between ces in the taste bud. When sweet, bit-

ter, or umami tastants excite taste buds, ATP secreted rom re-

ceptor ces stimuates gustatory aerent nerve fbers. At the

same time, ATP aso excites adjacent presynaptic ces and stim-

uates them to reease 5-HT and/or NE. ATP secreted during

taste stimuation has a third target, namey the receptor ces,

themseves. ATP, acting as an autocrine transmitter, exerts posi-

tive eedback onto receptor ces, increasing its own secretion

and presumaby counteracting its degradation by ecto-ATPase

(Huang et a., 2009; Fig. 3).

The 5-HT reeased by presynaptic ces aso may have

mutipe targets. One eect o 5-HT is to inhibit receptor ces.

That is, 5-HT exerts a negative eedback onto receptor ces.

The opposing eects o positive (purinergic autocrine) and neg-

ative (serotonergic paracrine) eedback in the taste bud during

gustatory activation combine to shape the signas transmitted

rom taste buds to the hindbrain. However, detais o how these

eedback pathways are baanced to shape the eventua sensory

output awaits experimentation and many questions remain. One

might specuate that 5-HT mediates atera inhibition, sup-pressing the output o adjacent receptor (e.g., bitter) ces when

a particuar (e.g., sweet) receptor ce is stimuated. Aterna-

tivey, the negative eedback oop may participate in sensory

adaptation by decreasing the aerent signa over time.

Other sites o action or 5-HT (and NE) possiby incude

the nerve fbers that orm synapses with presynaptic taste ces.

Quite possiby, there are parae purinergic and serotonergic

outputs rom taste buds and parae inormation pathways ead-

ing into the hindbrain. At present, this is ony a specuation

(Roper, 2009).

In summary (see Fig. 3), receptor ces detect and discrimi-

nate sweet, bitter, or umami tastants, generate Ca2+ signas, and re-

ease ATP transmitter onto aerent nerves. The ATP rom dierentreceptor ces converges onto and produces secondary excitation

o presynaptic ces, thereby integrating signas representing a

three taste quaities (Tomchik et a., 2007). It is not cear that the

secondary responses o presynaptic ces to sweet, bitter, and umami

stimui are necessary or identiying or discriminating these taste

quaities. Primary signas in presynaptic ces are ony generated

by sour tastants, and this is the ony quaity that is ost when pre-

synaptic ces are abated (Huang et a., 2006).

Cracking the taste code. Taste aerent nerve fbers

transmit inormation rom taste buds to the brain. How the acti-

vation o receptor and presynaptic ces during gustatory stimu-

ation transates into a neura code that specifes dierent taste

quaities (sweet, bitter, etc.) remains uncear. Two opposing so-

utions to this ogic probem are much discussed. On the one

hand, dedicated nerve fbers (abeed ines) coud transmit

each quaity, e.g., bitter ces, bitter fbers, and bitter neu-

rons at each successive reay in the brain. On the other hand, a

combinatoria system woud have quaities encoded by patterns

o activity across severa fbers. In the atter case, any given

fber coud transmit inormation or more than a singe quaity.

A third, ess-discussed option is a tempora code in which qua-

ity woud be denoted by a timing pattern o action potentias

such as occurs in auditory fbers.



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Kokrashvii et a., 2009a). The existence o these taste mecha-

nisms in the gut is perhaps not surprising, given the importance

o sensing the chemica nature o umina contents at a points

aong the GI tract. However, the fndings have generated new

excitement in understanding how the gut participates in detect-

ing and controing appetite in genera, and digestive processes

in particuar.

This work was supported by National Institutes o Health NIH/NIDCDgrants DC006308, DC006021, and DC010073 to N. Chaudhari;and DC000374 and DC007630 to S.D. Roper.

The authors have no conficts o interest to declare.

Other reviews in this series are: The cell biology o hearing (Schwander et al.2010.J. Cell Biol.doi:10.1083/jcb.201001138).

Submitted: 30 March 2010Accepted: 20 July 2010

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receptors (Chaudhari et a., 2009). There is aso the question o

transduction mechanisms or some o the ess-studied quaities

such as sour, atty, metaic, and astringent. Soving these may

require combining moecuar and popuation genetic anayses

on human or mouse popuations aong with more conventiona

expression studies.

Another area o intense investigation is how gustatory sig-

nas are encoded by the nervous system. The principes o sen-

sory coding rom the retina to visua cortex were eucidated

decades ago. We have a sound understanding o tonotopic and

computationa maps or the auditory system. Latera inhibition

and somatosensory receptive feds are we defned. Compara-

be insights into taste are acking and we sti do not understand

how the brain distinguishes sweet, sour, saty, and so orth.

I taste does not oow a simpe abeed-ine code, how are gus-

tatory signas transmitted and deciphered? Ongoing studies in-

cude the possibiity that taste is encoded in the time domain,

i.e., by the requency and pattern o action potentias in hind-

brain and cortica neurons (Di Lorenzo et a., 2009; Mier and

Katz, 2010). Other aboratories are exporing higher-order cor-

tica processing via unctiona magnetic resonance imaging toaddress the interaction between taste detection, preerence, and

appetite reguation (Ros, 2006; Sma et a., 2007; Accoa and

Careton, 2008).

A critica chasm in our understanding o taste is how gus-

tatory mechanisms are inked to mood, appetite, obesity, and

satiety. The obvious ink is that taste guides and to a arge extent

determines ood seection, with saty, sweet, and at tastes being

the main actors. A ascinating ink between appetite and moods

is that serotonin-enhancing drugs, commony used or treating

mood disorders and depression, were shown to inuence taste

threshods (Heath et a., 2006). Whether the mechanism o this

action depends on the inhibitory action o 5-HT in taste buds

remains to be determined, but the fndings are intriguing (Kawaiet a., 2000).

Cracks in the hard nut o appetite reguation are exposing

a new dimension o tastethe impact o appetite-reguating

hormones on periphera gustatory sensory organs. A number o

neuropeptide hormones activate hypothaamic and hindbrain cir-

cuits that reguate appetite. We are now earning that severa o

these same peptide hormones, incuding eptin, gucagon-ike pep-

tide, and oxytocin, moduate chemosensory transduction at the

eve o the taste bud. Circuating eptin, acting directy on taste

receptor ces, reduces sweet responses measured in taste buds,

in aerent nerves, and by behaviora tests (Kawai et a., 2000;

Nakamura et a., 2008). Circuating oxytocin, another anorectic

peptide, aso acts on taste buds (Sincair et a., 2010). Bood-

deivered satiety peptides may be idea candidates or integrating

sensory and motivationa drivers o appetite. Additiona satiety

peptides, incuding gucagon-ike peptide-1, are synthesized

within taste buds and act on taste ces or nerves (Shin et a.,

2008). This research might provide avenues into therapeutic ap-

proaches or obesity, and at a minimum urther hep expain the

seemingy insatiabe human drive to consume caories.

Finay, another new direction or taste research is the pres-

ence o taste receptors and their downstream intraceuar eec-

tors in sensory ces o the gut (Rozengurt and Sternini, 2007;

http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1083/jcb.201001138http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1073/pnas.0708927105http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1016/S0092-8674(00)80705-9http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1002/cne.20954http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1002/cne.20954http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1523/JNEUROSCI.1168-07.2007http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1523/JNEUROSCI.1168-07.2007http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1152/jn.00785.2009http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1126/science.1056670http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1113/jphysiol.2002.027862http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1113/jphysiol.2002.027862http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1038/39807http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1016/S0092-8674(00)80706-0http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1126/science.1174601http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1038/nature08783http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1038/72053http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.3945/ajcn.2009.27462Hhttp://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.3945/ajcn.2009.27462Hhttp://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1002/cne.10963http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1186/1741-7007-4-7http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1186/1741-7007-4-7http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1002/cne.10963http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.3945/ajcn.2009.27462Hhttp://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.3945/ajcn.2009.27462Hhttp://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1038/72053http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1038/nature08783http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1126/science.1174601http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1016/S0092-8674(00)80706-0http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1038/39807http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1113/jphysiol.2002.027862http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1113/jphysiol.2002.027862http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1126/science.1056670http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1152/jn.00785.2009http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1523/JNEUROSCI.1168-07.2007http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1523/JNEUROSCI.1168-07.2007http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1002/cne.20954http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1002/cne.20954http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1016/S0092-8674(00)80705-9http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1073/pnas.0708927105http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1083/jcb.201001138


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