Chemorecepce The Nobel Prize in Physiology or Medicine 2004 ,■' -■, "for their discoveries of odorant receptors and the organization of the olfactory system" Richard Axel 1/2 of the prize USA Columbia University New York, NY, USA; Howard Hughes Medical Institute Linda B. Buck 1/2 of the prize USA Fred Hutchinson Cancer Research Center Seattle, WA, USA; H ward Hughes Medical Institute b.1946 b.1947 7TM receptory Metabotropní signalizace E.coli (Repell anť) ^ Periplasm*: space Inner membrane J> Flagellar motor clockwise motion Periplasmio space Inner membrane Cytoplasm Flagellar motor anticlockwise motion Figure 10.6 Molecular signalling in the E. co/f chemosensory system, (a) The Tsr receptor-transducer protein accepts a repeilant molecule (Leu). CheW and CheA are activated ČheA accepts phosphate from ATP and passes it on CheY. CbeY diffuses to the flagellar motor and induces a clockwise rotation and hence tumbling. CheY is eventually dephosphorylated by CheZ. (b) The Tsr receptor-transducer accepts an atiractant molecule (Ser). The consequent conformational change Inactivates CheA and CheW so that CneY remains unphos-phoryiated and consequently inactive. The fiagelium resumes its anticlockwise motion and the bacterium swims smoothly forward. A = CheA; W = CheW; Y = CheY; 2 = CheZ. Data from Bourrett, Sorkovich and Simon, 1991 E.coli Outer membrane Cel] wall peptidoglycan Periplasm«: space Inner membrány Inner membrane Cell wall Outer membrane Che Y protein accessory olfactory bulb (AOB). vomeronasal organ (VNO) main olfactory epithelium (MOE) consists predominantly of ciliated olfactory sensory neurons (OSNs), which project to the main olfactory bulb (MOB) tu í bus oifactorius regio o! fsctori3 vzduch A. Nosní dutina a čichový orgán vůně vrstva hlenu kationtový kanál C. Transdukce čichového podnetu of f actor i a vzduch B, Čichový epitel (podJe Andrese) čichový podnet* Ľ-1 U c w o 100- > CL "J" 4ŕ 4T ^ 0- 3 T 0 ^ ^ čas po začátku podnetu [s] D. Adaptace čichu Figure 7.7 Olfactory epithelium {A} Schematic cross section of olfactory epithelium. (B) Scanning micrograph of a dendritic knob and dendrites of a human olfactory receptor neuron. Magnification: 1R,500><. (From Morrison and Costanzo, 1990.) [A) ■ Olfactory cilia Dendritic knob (B) 1 S us ten tii cu I fl r * Basal cell tulí Microvilli Dendrite Receptor ceil Receptor fljtons olfactory bulb DORSAL VIEW cerebral optic ... . „ hemisphere tectum cerebellum medulla olfactory bulb (a) SIDE VIEW 1.6 mm olfactory bulb DORSAL VIEW cerebral optic , „ , „ hemisphere tectum cerebellum ^dulla ir\ olfactory bulb (b) i___________________i 3 mm SIDE VIEW fornix frontal I i ' i k- septum olfactory bulb thalamus hipptiCEimpus reticular formation Hypothalamus špina! cord ire 10.1 The limbic system (the main limbic system structures are shown mammillary body v.:*. JrtffiJ Kil iíi-ll-.iiii VÍĽfc i ^IriiĽUii-v "hulh-. Human Silk" view / DliILliiii *íľw 6 hwiH NEUROBIOLOGY Gary G. Matthews SENSORY PROCESSES 385 (a) increase in cAM P Extracellular fluid Olf.it ttir y tum iron Cilia of otfacforv neuron Figure 13.36 Olfactory transduction mechanisms in cilia membranes of olfactory neurons (a) Many odorants act to increase cyclic AMP.The odorant binds to an odorant receptor on the ciliary membrane; the receptor activates a G protein to activate adenylyl cyclase, producing cAMP. Cyclic AMP binds to and opens a cation channel, allowing entry of Na' and Ca2- ions to depolarize the cell. Ca2' binds to Ca2*-activated C\~ channels, augmenting the depolarization, (b) Some olfactory responses increase IP^.This mechanism also starts with odorant binding to a G protein-coupled receptor, but in this case the G protein activates phospholipase C,forming JP3 from PIP^ (see Figure 12.21). IPj binds to and opens a calcium channel, letting Ca2+ enter to depolarize the cell. As in (a), Ca2+-acti-vated Cl^ channels augment the depolarization. Olfactory, Ciliumof ™ePtor'„ oifacloryN neuron Odorant molecule Adenylyl Cation cyclase charuiE Ca2 -activated, CI" channel h) Increase in [P3 Extracellular fluid Olfactory. Oliumof re^P^A (>ifacloryv neuron ř Odorant molecule Oilcium^ channel Ca2+-act-ivatild Cl~ channel \ ' Aktivace Adenylyl cyclase (ill) Cyclic nueleotide-gätéd channel independent chloride channel Od or ail t receptor Cyclic nucleoti de-gated channel Adaptace, terminace a modulace CliuniiĽil ■LiUlĹIITĽ A \ Odciniiil tudfeťUfc CIlL-lISĽjt -■- i_~i.ii- I! ocfjiiftr iiii-ikiulŕ :\ pr V * iri.u-u. . rcci'i-:. ■ nriimn hj-uícy ľBíípli^ PK-|lrTin <2ä"-j/ jfi. Eta«awJbyhíitiiXiindY ■ ■■;- ■■ :■■.. iiil-IľľuIľs A- Dcwdnl «riy by X _«ftciainnly hy V Dututf Lil bv ih-iLlii!iX mir Y b Rl-m-k &S--1-Í NEUROBIOLOGY Gary G. Matthews r A. Olfactory pathway and olfactory sensor specificity 1 Nasal cavity Olfactory bulb 2 Olfactory pathway Fila olfactoria Gjfßctary region Granular cell Mitral celt Reciprocal synapses (+/ -) 3 Sensor specificity (example) ra u gj M "o •M en CZ OJ ortho meta CH i ■:hj ........ ........ CH, Cttj ■CH1CH3 f >-ťHÍĚH3 CH, CHj ........ ........ ........ ........ -1 v—. oiŕM^oij chj- ........ .......1 ........ ........ (AfterK.KatohetJl.) Olfactory bulb (After K. Mori et al.) hsrirli-iinerulur ■xlb Mitral cclfca { <» i ■- -i ;-_ii ii- i.-i ii i «Ik b NEUROBIOLOGY Gary G. Matthews 'jNlllul..' LL-Il ťJľailulĽ COll Tu olbcrury rafter jz< i:e Konvergence na příslušný glomerulus Turbinates MOE = main olfactory epithelium. OB = olfactory bulb. AOB = accessory Olfactory bufb-VNO = vomeronasal organ. ■ : Uii;[nr. Gkrrmrui^ Mucus To- lateral tdfaclwy bdel Podobnost architektury sensorických obvodů a drah A. RETINA B, OLFACTORY BULB Comparison between simplified basic circuit diagrams of the vertebrate r bulb. (After Shepherd, 1978) A Olfactory bulb Olfactory receptor cell (ORG) Centrifugal fibre Olfactory epithelium Figure 13.7 Olfactory bulb, (a) The figure shows olfactory axons passing through the cribriform plate to end in glomeruli in the olfactory bulb, (b) Basic circuit of the mammalian olfactory bulb. Layers: EPL = external plexiform layer; GL = glomerular layer; GBL = granule cell layer; OT — olfactory tract; MCL = mitral cell layer. Cells: G^ = deep granule cell; GE = superficial granule cell; M = mitral cell: PG = periglomerijlar cell; T = tufted cell. Inhibitory cells stippled. Simpiified from Á^unq SAonßueo A>|unq k f iuuu>|eujw A>|unq \\ (5) lujeiodia luieiuoziJOH1 riAJ9u OD3AO».e.izÄuoxy ojpep 9upuoqooi|iy\j CZG-I 3Aouejquj3i/\j eA0;U3Wßlr| JÍĽĽĽpkír LypcA RuocpOúr \ypc ]'i Ruwťpfcír IVjtt! Cľ Ratcx-tiClii Cvpc D Překryv B Olfactory neuron response QN1 QN3 QN4 Lliňiŕd 4ttUh ,r.|'. UlíkCwyBulb i ľ- Ľorm A Odor ligands z Glomerular connectivity G1 G2 G3 G4 Proj£jf0n M1 M3 M4 output „Zostrení" naladění ve vyšších patrech dráhy Také adaptace může být na úrovni vyšších pater smyslové dráhy RECEPTOR CELLS MITRAL CELLS miiimmmi II I I M J I I I I. ODOR A (High Concentration) ODOR A (Low Concentration) ^_L± I I 1 I III I I II ODOR B -* -I I I I I I ODOR C - -Ml___I I í I l i Fig. 11.11 Extracellular single-unit recordings of responses to odors of receptor cells (left) and mitral cells (right) m the salamander, showing different types of responses and different temporal patterns of activity. (After Kauer, 1974, and Getchell and Shepherd. 197M tom i x frontal _. I ľ I k- Septum o! factory bulb thalamus hippocampus reticular formation < hypothalamus spinal Cord e 10.1 The limbic system (the main limbic sysLem structures are shown n mam miliary body FrtMtUJ ťŮťtifcl IlUSJĽI-M-lĽXh t NtůdLiLJí-^iiil inJĽUŕUh ■IlIlj.LjhiUril t I p.JlílKhSrtilT | t cpiľJicfiian Response specificity to size and composition of odorant molecule a) pheramone receptor of Mam&stra c HO OH CHC AC Ac — a£«la:a •üiiasüsiiiiiw-r. tw-at* P. 20 action 40 pot&rrt {nurnbai &Ü iata odorants boinhvcol stimulus electro -antennogram -j i« sensory neurons I Mill-! I IH II i—-< «111 Mil- till I I li— #H------ 4fH--------- I I I 4rilh*riM pctfWtTKA —r -1 olfactory receptor neurons terminate in antennal lobe glomeruli from antenna retina lamina\ mtenngf honeybee mftrlulla Antennal lobe: two major classes of neurons local Interneuron projection neuron (temporal and odor discrimination) «•*" JjIWJIJUUULJLal. ____________n________n________*» *________n---------------------------------------------- biCLicculin (GÁBA antagonist cholinergic sensory afferents bicuculline - sensitive receptors . Y ±í \ GABAergic — I p|SI LNs bicuculline - insensitive excitatory pathway air Even when following an odor trace, perception is discontinuous intact iw 4 4f_ *T %■ Or only 1 antenna ¥f antennae crossed Hangartner1967 resolution is limited Antennal nerve electrical stimulus ipsp^ 1WJUUU. i j\________n. 1LJULIJA_J1L _n____n____n____n____n_ Ji__n__n__n__n. rHIU—■ . < ■*- ji__n__n__n__n. ^t—-v+i------ J1JTJUVL pheromone stimuli PNs, temporal resolution Glomeruli responses odorants' structural properties (chain length, residues, polarity etc.): odor map TV)i > ■ ! Apis mellifera, ■"■" antennal lobe carbon chain length C-10 O 20 iO 6€ BO ILMft response írlensÉy »rocessed by Afo different j— olfactory y^ receptors ODOR fM V | SPACE/m^* | y \ V *y MACROGLOWERULůií COMPLEX ANTENNALI LOBE output inecf-orosenisoiy Input ANTENNA neurons PROTOCEREBRUM MOTOR SYSTEM 4> visual etCn Hildebrand 1996 ♦.▼/Ä í*^ílI«JÍK{í spectra than receptor neurons ORC2 ORC t PNI i 0FC4 U 1 ORC response ORC i OHCÍ ORC3 A A A A a PN2 VV PN3 a odor ligarxls z PN response PNI n PN2 A PN3 specialist (e.g. pheromone) 'ordinär/ PNs v a odor llgands 2 G. Hildebrand1996 Vomeronasální, Jacobsonuv orgán Turbinates MOE = main olfactory epithelium. OB = olfactory bulb. AOB = accessory Olfactory bufb-VNO = vomeronasal organ. ■ : Uii;[nr. Gkrrmrui^ Mucus To- lateral tdfaclwy bdel Hjernen Lugtkolben Lugtepithelet Naesehulen Vomeronasals organ / organ BioSite 14^8,03 (a) (b) Vomeronasal organ — r VÍRs + MHC ^ VIRs m Olfaclory epithelium Olladory receptors MRs l2Rs Olfactory receptors u«ü5 Gustatory receptors The location of chemosensory organs in the mouse and Drosophila. (a) A sensory neuron in the olfactory epithelium of mice expresses one of about 1,000 olfactory receptors. Neurons in the apical and basal layers of the vomeronasal organ express distinct, unrelated classes of G-protein-coupled pheromone receptors (V1Rs in the apical and V2Rs in the basal layer). In addition, a small family of MHC class I-like molecules is coexpressed with V2Rs in neurons of the basal layer. The taste cells in the tongue, palate and pharynx express other classes of GPCRs, one encoding sweet-taste receptors (T1Rs) and one encoding receptors for bitter compounds (T2Rs). Note that V1 Rs and T2Rs are related to each other, as are V2Rs and T1 Rs, respectively, (b) The olfactory neurons of Drosophila are located in two pairs of appendages in the head, the third antennal segment and the maxillary palps, and each neuron expresses very few, possibly just one, of the 61 olfactory receptor genes identified so far. The gustatory or taste sensory neurons are located in numerous organs, including the two labial palps on the head, internal sensory clusters in the pharynx (not shown), all the legs and the anterior wing margin. Each neuron expresses a few, possibly just one, gustatory receptor gene. A few gustatory receptor genes are also expressed in olfactory neurons of the antenna and maxillary rpalps. Čich a chuť GB.c Chuť 1 "n P pil *> YJ^l ^r% \ ***" i ■■^p* >v ^■^^^^■#4Afl ■■■La. / 1 v ■k^>B ■■^k^ 1 a Taste pore r Hal TRC Bitter Salty Sweet Umami Sour v „pfiltopcch" ubkLopiijFCiťti jrjiŕJi omliálnl tyl. mguji im chuLt bufltŕ. Mflídfj meri papuumi ytlhůajc (IL?, vyluruvaoý iliiyj.tnL umi^tŕnjŕmi rj l>ári irchto míier. t"h«íos.r nUü'lcYuly sc rniHi y (Otiůco vlhkem pwvUcdi ncjpri? r u ipi-yl.it a ieprv< fMMt it mohou chiito-LČ pfltisrty droit aviit. UtOVÍ PO H A VO^ ťí- "Synapw se synaptic vá -^Bazáfnk &ur** C E. Evaluation oftaste stimuli 100i- o) CD TO un TO CD 100 0 12 3 Relative stimulus concentration (After Pfaffmann) A- Sj]l-pnfli?rrínu Off ■>l, 1 / 1 li ■ M <]ET" \ &U4JI N S'.vľľt [MllĽľ l!ĽiHJ«-|l|_ Stimule I I.I.- OFF *m ..1 1 !hill\ jT ^ Suur f \ Bittet \..-w . _l SuilMřCV iiĽur-u-D «dl t Time T« i hniiD J .SCicnul-j'- -.in I---------------------1 b NEURQBfOLOGY Gary G. Ntatíh*äw& '-•■ —. Labelled-line model A cross-fibre models Figure 2 | Encoding of taste qualities at the periphery. There are two opposing views of howT taste qualities are encoded in the periphery, a, In the labelled-line model, receptor cells are tuned to respond to single taste modalities — sweet, bitter, sour, salty or umami — and are innervated by individually tuned nerve fibres. In this case, each taste quality is specified by the activity of non-overlapping cells and fibres, b, c, Two contrasting models of what is known as The 'across-fibre pattern1. This states that either individual TRCs are tuned to multiple taste qualities (indicated by various tones of grey and multicoloured stippled nuclei), and consequently the same afferent fibre carries information for more than one taste modality (b), or that TRCs are still tuned to single Taste qualities but the same afferent fibre carries information for more than one taste modality (<), In these two models, the specification of any one Taste quality is embedded in a complex pattern of activity across various lines. Recent molecular and functional studies in mice have demonstrated that different TRCs define the different taste modalities, and that activation of a single type of TRC is sufficient to encode taste quality, strongly supporting The labelled-line model. Transgenní myši 80 - !g 60 re o u Gl u ta a i a té Depo 1 a ri za ti on c AMP Depolarization (e) Bitter Closed K channel \ Bitter substance C_f protein Decrease in cAMP Increase in Ca2< Increased transmitter release gure 1334 Taste-transduction mechanisms differ for different iste qualities All transduction mechanisms except the IP3 action in I lead to depolarization, which spreads to the basal end of the cell id opens voltage-gated Ca2+ channels to allow Ca2~ entry and trans-litter release, (a) For salt taste, sodium ions enter a taste bud cell trough amiloride-sensitive cation channels, directly depolarizing the %L(b) in sour taste, either H* ions enter the cell through amiloride-jnsitive cation channels, or they close K" channels to produce depo-rization. (c) Sweet taste is most commonly mediated by the binding fsugars to a G protein-coupled receptor, which acts via a G protein to ctivate adenyfyl cyclase and produce cyclic AMP. Cyclic AMP then actuates protein kinase A (PKA) to close a K~ channel (by phosphorylating Endoplasm i c reticulum it), producing depolarization, (d) The amino acid glutamate (monosodi-um glutamate, MSG) stimulates the taste quality umami (a savory or meaty quality). Glutamate binds to a G protein-coupled receptor (related to synaptic rnetabotropic glutamate receptors) to activate a phosphodiesterase (PDE) and decrease the concentration of cAMP.The decrease in cAMP leads to an increase in intracellular Ca2+ concentration, (e) Bitter taste mechanisms can involve a G protein-coupled receptor for bitter substances that acts via a G protein and phospholi-pase C to produce IP3. IP3 liberates Ca2+ ions from intracellular stores, eliciting transmitter release without requiring depolarization.Other bitter substances bind to K~ channels and close them to depolarize the cell. N:i Sicíliím '■•.••:■ A. Sílí Suyťaň* or tongue A Es ci cm tJty / } Itale «II pliiKinn BJÍB*fMir 1.,/rVNj." [ \ IflwMu* Lltil / ~A ^nj_ tiľi-fľ liber í I j i 11 Si ..II SUďJatiiO* 1i7nyuĽ Viicr-w u i ľ-- i i icrqini «11 b cbinncl IV.-.v VnirtTUi] L'llülllOl ;-| 0|H1 rynglu | ^^p { : S.ir. ■ ■ 1h:iV(.- ckanod NEUROBIOLOGY Gary G. Matthews '■-" Time BOlVĽ íiíof -U-U Sweet A eherne I De píl o«p3i i wy brifl J K+chijnnrf — Ph i j.-: pli niy Ktlc i L Jí* c h ura n e-] — ItaMC I > II-■.!:- 6 NEUROBIOLOGY Gary G- Maíthews í:»>i:i Cirwssmdon Lif b lo^tt: rweplnr «H B. s, m-ni,- M C>vlic iiuclcodide lxn*nťt; ť fun n d ť kŕmi Cyulle iraKleotid*" noí híinnil: tíliinflCl (ipHWll O r,i>u n i rcŕupGur ciíll *>UMdŕ b NEUROBIOLOGY Gary G. Matthews h ■j-.<>-- i— C. Gustatory pathways Postcentral gyrus Nucleus tractus solitarli Thalamus: Nucleus ventralls posteromedial is Hypothalamus SeeD. N. petrosus major Chorda tympani I Iiul-L.....S 1 l'l'ii'. -I PimlLiir iiu.:|irw. ELimtnc J ] VIl!lLu! I;i ^ fhlic-i snputi ■ J UL. ICUL n| I LI U I ELI ;■ li.IL! i i^Lj lLbllu y nllĽluuK !-.>[ I;i- !l- : npuEi ■ "liJítJjUC H Tlihlc hud*- ■■..f. :■ VII ■■..f'..- IK i*, i ii i; i U i »Ol s* 117 y mpul.-i h Gary G. M a t E h ewe £ivii CľilIhiL vjIľus TjiLvIi---HuciyituMüiKun' IhmiLi Ošiali*} ťorl« [_j.Iľi;iL huIľut Side w* Gaslnlory mrtŕí PrööL Ciriíň sjuľuhm Insula. 6 Gary G. Matthäus SťVIM Hygrorecepce lOOi- 50 Htmf Pore-less sensillum Cuticle Sensory dendrites Dense secretion 'Dry receptor' 'Moist receptor ^^Hv^iwuw 100% 0 T 10 0% 20 30 wW^JflfJ»^ 50 Time (sec) FIGURE 7-18 The "cold-moist-dry" triad sensory sensillum of the cockroach contains three bipolar sensory neurons; one neuron of the hygroreceptor responds to high humidity ("moist" receptor) and one to low humidity ("dry" receptor). The receptor cavity of the poreless sensillum is filled with a dense secretion. (Modified from Yokohari and Tateda 1976; Schalter 1978.) Termorecepce MesöcurlcJa EndocuTicte Sensory nůurort Piyurc 1 a, Diagram of Mehinvphitti (body length t O mm). The infrared pil organs, situated next to the coxae or the middle Jegs, ar« completely exposed during flights b.An infrared sensiilurru redrawn from ref. 3. 167 rŤíšj~ -W ~]33 msf -IrírVIriMf 1_F7 ms ----Wr- ---------irv-n- IS msfr~ vv - J4 ms|~ + ^flisj- ^r 30 ma Figure 2 The responses of a neuron, recorded from the pit organ, to various infrared stimuli. Bach trace shows the original response lo one stimulus. Horizontal bars indicate exposure times. Each IrinJ was repeated three limes. The number of action potentials decreases with decreasing stimulus du.raci.oni 2 ms was sufficient to general« a response. If the mirror was covered, no response was recorded at any of the infrared intensities and shutter speeds tested. pass infrared filter [50% cut-on at 1.8 juliti} and neutra I-de n si t y filters. At a radiation intensity of 24 m W cm " ; singie neurons a Spinal cord and dorsal root ganglion Low-threshold mecha noreceptors Dorsal horn Temperature and pain receptors b Skin Merkel cells Meissners corpuscle Pacinian — corpuscle Epidermis { Dermis < Hair-root plexus Ruffini's endings Free nerve endings Hair Follicle \tentral horn \ L '; Skeletal muscle \ 1 i I /Afferent í fibres- í ,^ Epidermis Dermis Efferent fibres Figure 1 | Anatomic and functional organization of touch, ä | Spinal nerves Formed by the joining of afferent (sensory) and efferent [motor) roots provide peripheral innervation to skin, skeletal muscle, viscera and glands. Arrows denote the direction of incoming sensory and OLitgoing motor impulses. The cell bodies of motor neurons are located within the ventral horn (Jaminae Vll-IX) of the spinal cord. Cell bodies of sensory neurons are located in the dorsal root ganglia (DRG). Within the DRG there are subclasses of sensory neurons known as proprioceptive (blue), low-threshold mechanosensitive fed) and temperature- and pain-sensing neurons (green). These neurons project centrally to dorsal horn internet-irons (laminae I—VI oFthe spinal cord) and peripherally to target tissues. Proprioceptive neurons (blue fibre) project to specialized structures within target tissues such as muscle, and sense musde stretch. b | Low-threshold mechanosensitive neurons fed Fibres) project to end organs that transmit mechanical stimuli. Five types oFmechano-sensitive assemblies have been described and are illustrated in the figure. Temperature and pain sensing neurons (green) do not project to specialized end organs; instead they terminate as free nerve endings in all layers of the skin, and near blood vessels and hair follicles. c | Section of skin showing Free nerve endings (green fibres) stained with the pan- n euronal marker PGF'Q.S. The nudei of skin cells are stained (blue) with 4,6-diamidino-2-phenylindole (DAPI). Free nerve endings are found in both tine epidermal and dermal layers._________ 40 ;■: > 20 TO - Cold fibres 20 25 30 35 40 Skin temperature ("'C) Figure 2 | Average discharge frequency of individual cold-and warm-sensitive fibres in response to changes in skin temperature. The dotted line indicates the normal skin temperature (33°C). Cold-sensitive fibres respond only to cooling, whereas warm-sensitive fibres respond to warming. Neither type of fibre responds to mechanical stimulation. Adapted, with permission, from REF. 13 © (1969) The Physiological Society. Anktn il TrpmS Trpv3 Trpv4 Trpvl Trpv2 L L [_ [1 TRP domain o Ankjrin domain TrpmS (CMR1) ■- ' 20 30 Temperature f^Ol Figure 3 | Domain organisation and temperature thresholds oF temperature-activated transient receptor potential ion channels (therrnoTRPs>. a | TRP channels are composed of E*ÜK | 111. ii i . - ii hi iiLimi iť-^.|ja i n lil ig ui iiĽ=- i=ii kJ LylĽLíkd^ 11 íl. ai 11 ii lu fcii ilI c-lj tjtjKy I Lun nil li. Sui rKTRPa also have variable n um bers of an ley rin repeats at the amino terminus, or a conserved TRP domain of 25 amino acids after the transmembrane regions, b | Temperatures ranging From noxious heart to noxious cold activate several members oFthe TRP farnify. The cooling compound menthol and capsaicin fJJne hot ingredient oF chilli pepper) act as non-thermal activators of Trprn3 and Trpvl. nespectivefy. The thresholds of activation and maximal activation are based on activity of these channels in heterologous systems; some oF these thresholds are averaged values From different studies. Dashed lines indicate an uncertainty in the exact slope of the lines.