jysJové irsinstiukoB-jsik podnety vstupuji do nervového sy Všech 5 pohromadě Kanály - prostředek udržování integrity buňky a komunikace • • - sacharidy místo delece fenylalaninu \ á II oblast vázající T nukleotidy cytoplazrna" / . ,, , ■ r regulační oblast oblast chloridové vázající * ionty nukleotidy fosfátová skupina Po ukolvení v membráně se protein CFTR složitě přizpůsobuje - vyb/áří kanálky, kterými mohou přes membránu proudit chloridové ionty. V cytoplazmatické části proteinu jsou tři regulační oblasti, které se podílejí na uzavírání a otevírání póru. Kanálek se otevře jedině tehdy, když se na CFTR navážou dvě molekuly ATP a zároveň je fosforylována třetí regulační oblast. U mutovaného proteinu je jedna z oblastí vázajících ATP intaktní a membránový kanálek se neotevírá. epce - Zrak t Outer segment coll membrane Figure 13-14 Phototransduction closes cation channels in the outer segment of the photoreceptor membrane In the dark, the cation channels are kept open by intracellular cGMP and conduct an inward current carried largely by Na~>When light strikes the photoreceptor, these channels are closed by a G protein-coupled mechanism, O Rhodopsin motecules in the disc membrane absorb light and are acti- vated.© The activated rhodopsin stimulates a G protein (transducin in rods),which in turn activates cGMP phosphodiesterase.©The phosphodiesterase catalyzes the breakdown of cGMP to Sŕ-GMP. O As the cGMP concentration decreases, cGMP detaches from the cation channels, which close. 93824936334� t?uut£: *6fí>ír** phototransduction cascade. Insei: crnss-Hcctiun -uf a Dpfr$Qf}fiiIů THülaruigmter rhabdomere (electron niicruijraph cuurtesy of Dr A Polyanovsky), which is composed of sume 30000 microvilli, each approximately 1-2 U m in lenijjth and fifl nm in diameter. Each niicruvilluH contains approximately 1000 mulecules nf rhndopsin and most elements o:' the photntransiluctinn machinery. An enlargement nf ihe circled area in the inset, shuwinjj tbe base of one microvillus with associated phototransduction machinery, is shown schematically in the main figure. Activation: {I) phntuisumerizütion of rhodupsin tu mesarhndopsin [Rh—?M, encudcd by the ninui: o^enc) activates heterutrimeric Gq prntein via fiTP-ODP cxcbamje, releasing the fp^ft suhunit Cienes and mutants for bnrb 01 (tlgtf) and ß (gha) sobunits have been identified, (2) G^Ct activates: phosphulipase C f PLC; m}/pA e^ne), ^eneratinc; inosit-ul I ,4,5-trisphosphate flnsPj) and diacyl ojvcerul (DAG) frum phusphatitlyl i nositel 4,5- bisphusfitiate (PTPi). DAG is also a pntential precursor fnr polyunsaturated fatty acids (PIJFAs) via DAG lipase fu^ne yet to he identified in any eutary-ule). (i) Two classes of licjit-sensitive channel (TRP and TRPL; ľjjy and tľpf ^enes) are activated hy an unknown mechanism. Several components nf the cascade, including the ion channel TRP, protein kinase C (PKC, rnaC gaic) and PLC are cuordinated intn a sijmullinc; complex by the scaffolding prntein, TN AD, which contains five PDZ domains. {4} At the base nf the microvilli, a system uf submicrovillar cistemae f SMC) has traditionally been presumed tn represent Ca2: stores endowed with TnsP.i receptors [InsPj-R.; dip ^ene") and smooth endoplasmic reticulum Ca-1 -ATPase;, however^ the SMC may play a more important rnle in phosphuinnsitide turnover (5J: DAO is converted to phosphatide acid {PA) via DAG kinase irdgA o^enc) and to CDP-DAG sin CD syndiase (r:crv u^ne) in the SMC. After cunversiun tn phosphatidyl inusitnl (PI) hy PI synthase, PI is transported hack tu the microvillar memhrane by a PI transfer prntein [itlglt u;ene). PI is converted lo PIP: via sequential phosphurylation f PI kinase and PIP kinase). CEf4-ATPa*e Cu2'store SMC Signalplex Rhodopsin \ NI N AC ■t« Wi »•••»• ...... l>Vl > * * Cytoskeletal core Translokace TRP Čich insight review articles Figure 2 Odorant receptors are the Jewel of olfactory research In the past 10 years. The odorant receptors comprise the largest family of GPCRs. In mammals, odour receptors are represented by as many as 1,000 genes and may account for as much as 2% of the genome. Sequence comparison across the receptors has revealed many regions of conservation and variability that may be related to function. ar In a Hsnake' diagram showlngthe amino adds for a particular receptor (M71), those residues that are most highly conserved are shown In shades of blue and those that are most variable are shown In shades of red. The seven «-helical regions (boxed) are connected by Intracellular and extracellular loops, b, Aschematlc view of the proposed three-dimensional structure of the receptor based on the recently solved structure or rhodopsln. Each of the transmembrane regions Is numbered according to t hat model. The conserved (blue) and variable (red) regions are sketched onto this qualitative view and suggest that a llgand-blndlng region may beat least partially formed by the variable regions of the receptor, c. Mammalian odour rKeptors a re related pliylogenetlcally to other cliemosensory receptors. In the tree depicted here the numbers refer to the approximate number of receptors In each family. ORr Odorant receptors: T1 Rr T2H taste receptors: V3Rr vomeronsal receptors: DOR, DGR, Dtosopftila odour and gustatory receptors: worm refers to C. etegansL The scale bar Is a graphical distance equal to 1 D9£ sequence divergence. But this ambitious experimental programme lias barely progressed, owing to the puzzling difficulty of expressing ORs in heterol- release that was measured by fura-2 imaging. Finally, FishOR-100 Mammal ORs -50Ü-1.OÜ0 Bird ORs? T2Rs? TIR5 -80 V2Rs-1QQ VIR5-ISO DOR 61 DGR-GO Worm OR -1.000 T.W1.-. ŕ-u- UJ.-rU fUw Other GPCRs -400 in mammal SENSORY PROCESSES 385 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 adenyJyl cyclase, producing cAMP. Cyclic AMP binds to and opens a cation channel, allowing entry of Ma1 and Ca2- ions to depolarize the cell. Ca7 ' binds to Ca2""-activated CI" channels, augmenting the depolarization, (h) Some olfactory responses increase IP3."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 PIP2 (see Figure 1 2.21). IP3 binds to and opens a calcium channel, letting Ca2+ enter to depolarize the cell. As in (a), Ca^-acti-vated CI" channels augment the depolarization. Extracellular fluid (h) Increase in W% Extracellular fluid Olfactory t ."i I in of olfactory neuron (a} Increase in c AM P Figuře 3 Sensory transduction. Within the compact cilia of the OSNs a cascade of enzymatic activity tra nsd uces the binding of an odorant molecule to a receptor into an electrical signal that can be transmitted to the brain. As described in detail in the text, this is a classic cyclic nucleotide transduction pathway in which all of the proteins involved have been identified, cloned, expressed and characterized. Additionally, many of them have been genetically deleted from strains of mice, making this one of the most investigated and best understood second-messenger pathways in the brain. AC, adenylyl cyclase; CNG channel, cyclic nucleotide-gated channel; PDE, phosphodiesterase; PKA, protein kinase A; ORK, olfactory receptor kinase; RGS, regulator of G proteins (but here acts on the AC); CaBP, calmodulin-binding protein. Green arrows indicate stimulatory pathways; red indicates inhibitory (feedback). CNG channel AMP institjni review «iruuit;** Turbinates Figure 1 Functional a n atomy and structure of the early olfactory system. In one of the clearest cases of function following form in the nervous system, the anatomy and structure of the early olfactory system reflect the strategy for discriminating between a large number of diverse stimuli. ar In a sagittal view of the rat head, the main olfactory epithelium (MOE) is highlighted in green. The turbinates are a set of cartilaginous flaps that serve to i ncrease the surface area of the epith el i u m; they are cove red w ith the thi n olfactory neuroepithelium (shown in b). The cells of the MOE send their unbranched axons to targets i n the olfactory bulb (OB) known as glomeruli (shown in c). The vomeronsal organ (VNO) is shown in red, and the targets of the VSN axons are in glomeruli in the accessory olfactory bulb (AOB). The structure of the nasal cavity is optimized for exposing the largest possible surface area of sensory neurons to a stimulus stream that is warmed, moistened and perhaps concentrated by sniffing. b. The olfactory neuroepithelium is a relatively simple tissue consisting of only three cell types: olfactory sensory neurons (OSNs; the only neuronal cell type), supporting or sustentacular cells (a kind of glial cell which possess microvilli on their apical surface), and a stem-cell population, known as basal cells, from which new OSNs are generated. cr Wiring of the early olfactory system. Each OSN expresses only one of the -1 r000 OR genes a nd the a xons f ram a 11 eel I s expressi ngthat particular řece pto r converge onto one or a few 'glomerulir in the OB. The nearly 2r000 glomeruli in the rat OB are spherical knots of neuropil, about 50-100 ^m in diameter, which contain the incoming axons of OSNs and the apical dendrites of the main input-output neuron of the 0Br the mitral cell. Mitral axons leaving the OB project widely to higher brain structures including the piriform cortex, hippocampus and amygdala. Lateral processing of the message occurs through two populations of intemeurons: pehglomerular cells and granule cells. Mucus Glomerulus To lateral olfactory tract Odorants Receptors AAA Pattern of peripheral activation A-P ana en en □ ML □mľh Olfactory Bulb Although there are some 1,000 ORs, detecting the enormous repertoire of odours requires a combinatorial strategy. Most odour molecules are recognized by more than one receptor (perhaps by dozens) and most receptors recognize several odours, probably related by chemical property The scheme in the figure represents a current consensus model. There are numerous molecular features, two of which are represented here by colour and shape. Receptors are able to recognize different features of molecules, and a particular odour compound may also consist of a number of these'epitopes' or 'determinants' that possess some of these features. Thus the recognition of an odorant molecule depends on which receptors are activated and to what extent, as shown by the shade of colour (black represents no colour or shape match and thus no activation). Four odour compounds are depicted with the specific array of receptors each would activate. Note that there are best receptors (for example, red square), but also other receptors that are able to recognize some feature of the molecule (for example, any square) and would participate in the discrimination of that compound. In the olfactory bulb there seem to be wide areas of sensitivity to different features (for example, functional group or molecular length). This model is based on current experimental evidence, but is likely to undergo considerable revision as more data become available. Chemorecepc Tasty bud SENSORY PROCESSES 383 fa) Salt Extracellular fluid (b) Sour (c) Sweet Amilorid insensitive -cation channel—. Taste bud cell membrane A deny tyl cyclase B Closed K~ channel / Depolarization a&m Depolarization cAMP- Depolarization (ä) Umami Gl ti tain a tě PDE (e) BiUer Closed K+ channel V Bitter substance -hp?Y ON i_r protein Decrease in cAMP K+ Increase DepoJarization Ln Ca2 Phospholipase C ^># prp. G protein Increased transmitter řvliM.- ■ ígure 13+34 Taste-transduction mechanisms differ for different ste qualities All transduction mechanisms except the IP3 action in J lead to depolarization, which spreads to the basa J end of the cell nd opens voltage-gated Ca2"1' channels to allow Ca2- entry and transmitter release, (a) For salt taste, sodium ions enter a taste bud tell rough amitoride-sensitive cation channels, directly depolarizing the $ In sour taste, either H" ions enter the cell through amiloride-nsitive cation channels, or they close K+ channels to produce depo-rization, fc) Sweet taste Is most commonly mediated by the binding f sugars to a G protein-coupled receptor, which acts via a 6 protein to ctivate adenylyl cyclase and produce cyclic AMP. Cyclic AMP then acti-es protein kinase A {PKA) to close a K" channel (by phosphorylating EndopJasmic retieuLum Ca2 it), producing depolarization. (d)Jhe amino acid glutamate (monosodi-urn glutamate, MSG) stimulates the taste quality umami (a savory or meaty quality). Glutamate binds to a G protein-coupled receptor (related to synaptic metabotropic glutamate receptors) to activate a phosphodiesterase (PDE) and decrease the concentration of cAMRThe decrease in cAMP leads to an increase in intracellular Ca2+ concentration, (e) Bittei taste mechanisms can involve a G protein-coupled receptor for bitter substances that acts via a G protein and phospholipase C to produce IP3-IP3 liberates CaJ+ ions from intracellular stores, eliciting transmitter release without requiring depolarization.Other bitter substances bind to K+ channels and close them to depolarize thecelL Salty Sour Urnami Bitter Trehalose Predicted sweet Sweet receptor, (L-glutarnate) (sweet) receptor functional as heterodimer a Y N N N____________ ENaC/Degr ENaC, ASIC, Taste mGluR4r T2R family, Predicted receptor T1R3 (sac locus) T1R2/T1R3 others H C N, others others others ot Drosophila (rets 72-75) (rets 76,77) (rets 34r35) (rets 40r43) (ret. 94) (rets 47-49) (ret. 69) Figure 3 Transduction of bitter taste as elicited by a variety of ligands. Rs, multiple GPCRs of the T2R family coupled to the G protein gustducin47-49; a, a-subunit of gustducin6'57; p-y, G-protein subunits ß3 and 713 (refs 60-62); PLCß2r phospholipase C subtype61; lns(1r4,5)P3, inositol-1,4,5-trisphosphate59; PDE, taste-specific phosphodiesterase58; cAMP, cyclic adenosine monophosphate59; cGMR cyclic guanosine monophosphate59; sGCr soluble guanylate cyclase55; NOr nitric Figure 4 Molecules involved in the transduction of sweet taste. Two separate sweet receptors are shown, but the possibility that one receptor activates both of the transduction pathways100 is not excluded at this stage. R, candidate receptor(s)72-75; AC, adenylate cyclase61,8207; cAMR cyclic adenosine monophosphate21; PDE, phosphodiesterase, inhibitor W7 (ref. 89); CAM, calmodulin09; PKA, protein kinase A, inhibitor H89 (ref. 89); PLC, phospholipase C89; DAG, diacylglycerol; lns(1,4f5)P3, inositol-1,4,5-trisphosphate21; PKC, protein kinase C, inhibitor bim (bisindolylmaleimide)89. For crosstalk between pathways and effects of inhibitors Non-eater Substrate 1 Figure 2. Assays of feeding behavior. (A) Two-choice preference assay. Flies are first starved for a day and then provided with the choice of two chemicals, presented on a multi-well plate at specific concentrations in an agar medium. The two food substrates also contain different tasteless compoiTkds that have intrinsic colors, For example, sucrose might be added n one half of the weis on a titer plate, along with the sulforhodamine B dye (red) and trehalose, along with an erioglaucine dye (blue) on the other half of the wells. The feedhg is carried out h darkness (to exclude any rrf bence of color preference) and the abdomen of the flies is inspected visually. The number of flies feedhg on either substrate (red or blue abdomen) and both substrates (purple abdomen) are used to determine the feeding preference index: PI (sucrose) = N(red) +■ 0.5N(purple) / N(red)+N(blue)+N(purple). (B) Proboscis extension reflex. This does not measure feeding behavior, but rather a reflex behavior associated with feeding. Starved flies are narcotized and immobilized and then let to awaken and recover. Upon satiation with water, the forelegs of the fly — the GRNs — are stimulated with a chemical and the number of proboscis extensions are counted over a short period directly following the stimulation. The proboscis is usually withdrawn (top), but upon stimulation of the foreleg with a feeding stimulus (for example a sugar solution), is frequently extended (bottom). The number of extensions is directly correlated with the attractiveness of the stimulus. N on-discriminating SLbstrate 2 -.1 * í fj Current Biology echanorecep mat, s t ■*-------Deflection------->• Figure 1 General features of mechanosensory transduction. A transduction channel is anchored by intracellular and extracellular anchors to the cytoskeleton and to an extracellular structure to which forces are applied. The transduction channel responds to tension in the system, which is increased by net displacements between intracellular and extracellular structures. Figure 2 C. eleganstouch-receptor structure and transduction model, a, View of C. elegans showing positions of mech a no receptors. AVM, anterior ventral microtubule cell; ALML/R, anterior lateral microtubule cell left/right; PVM, posterior ventral microtubule cell; PLML/R, posterior lateral microtubule cell left/right, b, Electron micrograph of a to uch-receptor neuron process. Mechanotransduction may ensue with a net deflection of the microtubule array relative to the mantle, a deflection detected bythe transduction channel. Arrow, 15-protofilament microtubules; arrowhead, mantle. Modified from ref. 3. c, Proposed molecular model for touch receptor. Hypothetical locations of mec proteins are indicated. PVM ALM R PLML -...AVM PLMR Cuticle Hypodermís^ř Cuticle i Extracellular anchor (MEC-5) Transduction channel (MEC-4, MEC-6?r M EC-10) Stomatin-like (MEC-2) -Extracellular link (MEC-9) Microtubule (MEC-7, MEC-12) Figure 3 Drosophila bristle-receptor model. a, Lateral view of D. melanogastershowing the hundreds of bristles that cover the fly's cuticle. The expanded view of a single bristle indicates the locations of the stereotypical set of cells and structures associated with each mechanosensory organ. Movement of the bristle towards the cuticle of the fly (arrow) displaces the dendrite and elicits an excitatory response in the mechanosensory neuron, b, Transmission electron micrograph of an insect mechanosensory bristle showing the insertion of the dendrite at the base of the bristle. The bristle contacts the dendrite (arrowhead) so that movement of theshaft of the bristle will be detected by the neuron. c( Proposed molecular model of transduction for ciliated insect rnechanoreceptors, with the locations of NompC and NompA indicated. Shaft Endolymph Dendrite Socket cell Neuron Extracellular anchor (NompA) 3* I l=CZl=DQEr= CUT =i--------a—■—i=i—i=mrbz =i------b—■—m—i=pon= =i------tr-|—rrn^THXN =cnE CUE W Non-adapting j transduction channel Extracellular link Adapting transduction channel (NompC) Intracellular link ť^ Adaptation machinery Microtubule Figure 4 Inner-ear structure and hair-eel I transduction a model. af Gross view of part of the inner ear. Sound is transmitted through the external ear to the tympanic membrane: the stimulus is transmitted through the middle ear to the fluid-filled inner ear. Sound is transduced by the coiled cochlea. br Cross-section through the cochlear duct. Hair eel Is are located in the organ of Corti, resting on the basilar membrane, c, Sound causes vibrations of the basilar membrane of the organ of Corti; because flexible b hair-cell stereocilia are coupled to the overlying tectorial membrane, oscillations of the basilar membrane cause back-and-forth deflection of the hair bundles, d, Scanning electron micrograph of hair bundle (from chicken cochlea). Note tip links (arrows). er Proposed molecular model for hair-cell transduction apparatus. Semicircular „canals Stereocilia Tectorial membrane Adaptation motor Climbing + I Slipping adaptation | f adaptation Box 2 Figure Ha ir-cell transduction and adaptation. a, Transduction and fast adaptation. At rest (left panel), transduction channels spend -5% of the time open, allowing a modest Ca2- entry (pink shading). A positive deflection (middle) stretches the gating spring (drawn here as the tip link): the increased tension propagates to the gate of the transduction channel, and channels open fully. The resulting Ca2- flowing in through the channels shifts the channels' open probability to favour channel closure (right). As the gates close, they i n crease force in the gating spring, which m o ves the bundle back in the direction of the original stimulus. b, Transduction and slow adaptation. Slow adaptation ensues when the motor (green oval) slides down the stereocilium (lower right), allowing channels to close. After the bundle is returned to rest (lower left), gating-spring tension is very low: adaptation re-establishes tension and returns the channel to the resting state.__________________________________ PMCA — CaM- Pcd15- -A—< Myolc Actin Fi m br in Espin —- Myo7a — Harmonin PKA Vezatin Cdh23 Box 3 Figure Schematic illustration of identified hair-bundle proteins showing hypothetical locations of molecules implicated in stereocilia function. Myo7a, vezatin, Cdh23 and PKA may form the ankle-link complex. Pcd15 presumably also interconnects stereocilia. Myolc may carry out adaptation, whereas PMCA maintains a low Ca2" concentration. Actin, fimbrin and espin have structural roles; not shown is DFNA1, which may help form the cytoskeleton. Calmodulin regulates several enzymes within the bundle, including PMCA, Myo1 c and Myo7a. 30 Nocicepc b.bttuAVuVit ©Meianie WeidnEr 2DQ5 www.Li5tEnFarJay.ccrn í bolesti Figure 2 Polymodal nociceptors use a greater diversity of signal-transduction mechanisms to detect physiological stimuli than do primary sensory neurons in other systems. a, In mammals, light or odorants are detected by a convergent signalling pathway in which G-protein-coupled receptors modulate the production of cyclic nucleotide second messengers, which then alter sensory neuron excitability by regulating the activity of a single type of cation channel, b, In contrast, nociceptors use different signal-transduction mechanisms to detect physical and chemical stimuli. Recent studies suggest that TRP -channel family members (VR1 and VRL-1) detect noxious heat, and that ENaC/DEG-channel family detect mechanical stimuli. Molecular transducers for noxious cold remain enigmatic. Noxious chemicals, such as capsaicin or acid (that is, extracellular protons) may be detected through a common transducer (VR1), illustrating aspects of redundancy in nociception. At the same time, a single type of stimulus can interact with multiple detectors, as shown by the ability of extracellular protons to activate not only VR1, but also ASICs, which are also members of the ENaC/DEG-channel family. a Light (USUI ^* ^ ^ Odorants wwmü ..wwivm mm TTX-R (Nav1.B and 1.9) Figure 4 When nociceptors are exposed to products of injury and inflammation, their excitability is altered by a variety of intracellular signalling pathways. The figure highlights the vanilloid receptor (VR1) and tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels (Nav1.8 and 1.9) as downstream targets of modulation. Responses of VR1 to heat can be potentiated by direct interaction of the channel with extracellular protons (H+) or lipid metabolites, such as anandamide (AEA). VR1 activity can also be heightened by agents such as NGF or bradykinin, which bind to their own cell-surface receptors (TrkA and BK, respectively) to stimulate phospholipase C (PLC-y or PLC-ß) signalling pathways. This, in turn, leads to hydrolysis of plasma membrane lipids and the subsequent stimulation of protein kinase C isoforms, such as PKC-e. Both of these actions have been proposed to potentiate VR1 function. Prostaglandins (PGE2) and other inflammatory products that activate adenylyl cyclase (AC) through Gs-caupled receptors also enhance nociceptor excitability. This occurs, in part, by a cyclic AMP-dependent protein kinase (PKA)-dependent phosphorylation of NaJ .8 and/or Nav1.9. By activating Grcoupled receptors, opiates and cannabinoids can counteract these increases in excitability of the nociceptor, and produce a peripherally mediated analgesia. u C B (or opiate) etorecepce iontové kanály JD 1513 -»- ^■B B = 0 shluky nanokrystalu magnetitu i axon volné nervové zakončení Singletový stav Opsin-cis retinal / v základním stavu Tnpletový stav ISC rozpad recepce světla Trans retinal + opsin MP štěpí tripletní stavy a mění pravděpodobnost přeskoků intenzita MP 90 60 30 trorecepce Lorenziniho ampule AfKWi ctét FWtntd ctli bit*nwrt nwnbm Covering Cete Receptor Geis CapsiieWal Afferent Nerve »Pasivní - detekce napětí vznikající svalovou a nervovou činností »Aktivní - podobá se echolokaci •Navigace ^ •Detekce kořisti > v kalných vodách •Komunikace J Lorenziniho ampule - změna potenciálu otevírá Ca2+ kanály a stimuluje eflux mediátoru Facial nerve (a) Clusters o1 ampullae Dorsal branch Posterior fateral-line nerve Gillsfits Current path command center is I Gap junctions assurj maximizing signal ij pling of the medulki tor that determines I of electrocytes capali A few species, s| produce discharges [ bodies, whereas in [ range to mi IH volts td or kill prey, wherea^ for electrolocation " Some animalsl Tonic ampullary electrorc-ccptor Km R- Phasic tuberous clectroreceptor ransient receptor potential intra-membrane interaction module(s) cytoplasmic interaction module(s) niiiiiE I - PLC ^-HnsPí DAG ! DAG PI J FA © *r PhüsphöinoHitide ^ lumn-vcr l*d "V / DA& PIP* + ^M | ^B PA nsF, ^-jCDP-DAÍX^ tuftr J'l 1 * cJ" Ca24 store SMC Cet':-ATPase i VSiEC*C1.C»Tŕ| VartiISoid v«<Éc»cŕ.c«Ti: Receptor TRP V v» C4 CS C1 C3!ľV0 OAC-SvfThtvP mTRPCZ [TtumanTRPCZ n pit? u doge ne i V4 ťOTRPCJ VR OAC) VZfVRL 1.GRLV OTRPC2) LV1 LVňl.OTRPCl) Classical (short) TRPC jcolipins Í-líMCOLNI> Ht_ 1 .MC GL N 3.i ML2 jWCOLMÍj ■.-:>--.0m..^: D2LÍ) / P2 (IÍC2 PKffif> A.NKIM1 I Mela sta t in) M3 ihKlAA1616 LTRPC3). M*(CHAK2> ■.>ji rr- r.1 Vjr u:c i M7ICHW1.TRP-P1.IHL LTRPCTJ M*(bTRPCÍLTRPC2> MfllTrp-pe.CMRii ftU (hFLJ2QW1 LTRPC4.CAN) MSiMiM LTRPC5J Mel a sta ti n (Long)TRPM p TRP kanály Selectivity filter /------------\ (------------\ 4-------------\ (----------'S (------------\ TRPC TRPV TRPM TRPML TRPP N: N: N: N: N: 3^*1 0 S^iCH o 9 ■ 9 ■ C: C: C: C: Cr OOO DOO V J DOn V J l J ♦o TRPN f 1/ TRPA N: N: Otu-isj C: 9 * V J C: 9 ■ V J' Legend: OcaMtíndír« jjj Anfcyri n repeat O PDZ binding Q Cote*ffl3 domain Q Enzyme domain ] TRP Box ^^ tR retention motif op oc 140 _ 1 60 1201 E~50 1001 1 40 80 1 | 30 i 60 | 40 j Ť 20 Flo 1 0 20 g 0 "j © Mammals 109 E > o. ei* i K V fc lo. Figure 2 Activation range of human and Drosophila thermoTRPs. Indicative temperature range for activation of mammalian and Drosophila thermoTRPs in heterologous expression systems. Note that TRPM8 and TRPAl are activatedupon cooling, whereas all other indicated channels are heat activated. 2177173005488210490269 TempfC) V (mV) TenpfC) Figure 3 Temperature sensitivity is voltage dependent, (a) Normalized TRPM8 current in response to cooling at +100 and -80 mV. Note that at depolarized potentials, current activation occurs at higher temperatures than at more negative potentials, (b) Plot showing the open probability of TRPM8 in function of voltage at the indicated temperatures, (c) Plot of the midpoint of the activation curves iVy?) versus temperature forTRPVl and TRPM8. Adapted from ref. 41. Pel tie r elements mechanosensitivita fílWlí wmm - X>^ü. IUI II Ml IIIIP IUI \[\\\ IIII ■ ímw Klí .oini)i íäSiÉ *JU'. TRPC ^q/n trkR PLCy