jysJové irsinstiukoB-jsik podnety vstupuji do nervového sy Hranice ivého a ne-smyslového signálu > Co se děje na membránách smyslových ěk. iak mohou smyslové oodnět > Paralely se známými signálními drahan diferenciace, imunity, apoptózy > Společně využívané „vyzkoušené" funkce Po ukolvení v membráně se protein CFTR složitě přizpůsobuje -vytváří kanálky, kterými mohou přes membránu proudit chloridové ionty. V cyto plazmatické 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 071128 membránový potenciát © K -acetykholin vnější ligandy / intersľicium cyľosot a- < 5 protažení bu n eč-né membrány intracelulární rnetabolity intracelulární signálni látky Metabotropní transdukce Už jste se potkali s kanály? i— B. Diacylglycerol {DAG} and inositol 1A5-trisphosphate(IP3) as second messengers -. e.g., epinephrine (ot^p histamine {H-|), CCK, etc. Messenger binds to specific receptors Second messengers PIP2 (phosphatidylino- ® sitol 4,5-bisphosphate) s^lßh VWvWWV^ P^A AAAAAAA/V1 i f* "Pa (^s® (inositol 1,4,5- iX/Sfr tri s phosphate) ^Y4*' CftG (diacyl glycerol) yVWVWWH Cell response Neurons, exocrine and endocrine pancreas, platelets, liver, adrenal cortex, leukocytes, oocytes, etc. i- C Regulation of Cell Proliferation, Motility and Differentiation Ions Growth-promoting hormones Extracellular matrix Synthesis of growth factors Differentiation Form Migration Biosynthesis Adhesion Proliferation i— L Nitric oxide (NO) as a transmitter substance Messenger, — e.g., acetylcholine kinase /Activated Q-jp Activated Diffusion \ / Cytosolic guanylate cyclase CGMP Cell 2 (e.g., vascular myocyte) NO <- Ca2+ channel Cell membrane Calmodulin ^J sj Ca2+- J calmodulin complex i NOsynthas ŕ Arginine , NADPH Citrulline Celll (e.g., endothelial cell) I- A. Homeostasis of Volume and Electrolytes in the Cell H20 , Na+ 'it HaO V Na\ ATP --------- Amino acidsh . glucose, etc. ft cr Metabolism Na+/lO-ATPase K+ ©®5 ------------► In nerve and muscle cells: Na' channels lea2* H+ Nah 9JH-n ^Na+ 3Na+ Na+. Amino acids, glucose, etc. 7^ľt 10 \ K+ K+ ----------------► i- B, Necrosis Hypoxia, ischemia Poisoning (e.g. oxidants) Endogenous substances (e.g. glutamate) \ .... Phospho- Glucose °2 deficiency |ipase ^ deficiency .actate \ H+ 1 I Mitochondrial . ^ respiration Cell activity (excitation, transport) L f í ^- Anaerobic glycolysis 5l ATPI Y**" Membrane destruction Oxidants t ------------->H20 Macromolecules Cell swelling Inflammation Cell death i- A, Triggering and Development of Apoptosis Ischemia etc. TNF-oc Lack of growth factors Radiation Poisons CD95 receptor Glucocorticoids Caspases Sphingomyelinase Ceramide i Ras Rac p53 Tyrosine kinase Mitochondrial destruction Ca2+« DNA repair ^^ DNA damage Bax Bcl2 Cell shrinkage DNA fragmentation 1 !' * «tou* ffll 111 I y i Lii«j Ülii LIJ X ray krystalografie analýza sekvence AK Jak kanál vypadá An overhead view of a voltage-dependent potassium ion channel shows four red-tipped "paddles" that open and close in response to positive and negative charges. This structure, discovered by Rockefeller scientists, shows for the first time the molecular mechanism by which potassium ions are allowed in and out of living cells during a nerve or muscle impulse. Kanálv v molekulární fvzioloaii smvslu Kanály jsou odpovědné za regulaci membránového napětí a tedy klíčové pro přenášení nervových signálů. Nervový systém „vidí" jen to, změní kanálovou propustnost. Co se děje mezi receptory a kanály J Elektrolomcké V AkCni potenciál Generátorový *— &lren[ ^Recepturo vý 1 potenciál JL vlA potenciál 7i epce - Zrak f Outer segment cel] 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 Rhodopsm molecules 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 S'-GMP. O As the cGMP concentration decreases, cGMP detaches from the cation channel which close. Od 70. let obecné schéma G-proteinové signalizace {oj Retinal and vitamin A (b) Opsin ^\/ 3 H 3 TT | 3 >^C^ ^C" ^C^ _^<^ ^C^ /-CH.OH hÍ H H ! ; Complete structure of vitamin A (all-rrarcs) CH,C)H Condensed structure of vitamin A (all-trans) CHO Retinal (all-ŕroíis) Retinal (ll-cis) CHO Cytoplasm. Disc membraníí SENSORY PROCE1 Outer segment cell membrane Visual pigment (rhodopsin) Disc interior Disc membrane COOH Disc interior NH2 Prostetická skupina - chromofor nezbytná pro absorpci vyšších délek Chromofor ve funkci ligandu, světlo iniciuje Drosophila jako model zrakové transdukce: Zesílení -jediný foton Nízký šum ve tmě (spontánní termální izomerizace) Adaptace -106 Terminace odpovědi Nejrychlejší známá G signální dráha Fig. 1. Dr&bOfrfiiia mčiwt&gabtw photQtransdu.ction cascade. Inset: crosH-secbun uf ü BpfrsOßhiiü mzlanQgůxter rhabdomere- (electron micruijraph cuurtesy of Dr A Polyanovsky), which is composed of sume 30000 microvilli, eacli approximately 1—2 Um in leniti and fifl nm in diameter. Each microvillus contains approximately ] Qflft mulecules of ihndopsin and moHt elements of the phototransductinn machinery. An enlargement of the circletl area in the inseí, shuwiníí the hase or one microvillus with associated phototransduction machinery,, i h shown schematically in the main figure. Activation: (i) phníuisumerizutioii of rhodepsin tn metarhmlopsin (Rh—^^ encoded by the ninuli gene) activates heterntrimeric Cq protein vřu fíTP-GDP exchange, releasing the fl^fi. subuniL Genes and mutants for berth (Y. idgq) and ß (gl/a) subuniLh have been identified. (2) G^ activates phosphulipase C (PLC; iiQrp.A gene), irenerating inositnl i ,4,5-trisphosphate (InsPj) and diacyl glycerol (DAG) from phosphatidyl inositol 4,5- bisphusphate (PIPi). DAti is also a potential precursor fnr polyunsaturated fatty acids (PIJFAs) via DAG lipase (gene yet to he identified in any eLLkaryutc). (3) Two classes of light-sensitive channel (TRP ancl. TRPL; toy and tip! genes) are activated hy an unknown meclianism. Several components of the cascade, including the ion channel TRP, protein kinase C (PKC, inaC gene) and PLC are coordinated into a signalling complex by the scaffolding pre-tein, TN AD, which contains five PDZ domains. {4} At the base of the microvilli, a system of submicrovillar cisternae (SMC) has traditionally heen presumed tn represent Cai: stores endowed with TnsP.i receptors (InsPiR; itifi gene) and smooth endoplasmic reticulum Ca1:-ATPasej however, the SMC may play a more important role in phospliuinnsitidc turnover [$): DAG is converted to phosphatide acitl {PA) via DACi kinase {rttgA gene} and to CDP-DAO via CD synthase (ct/y gene) in the SMC. After conversion tn pliosphatidyl inositol (PI) hy PI synthase,. PI is transported hack tu tlie micrnvillar membrane by a PI transfer protein {itlgft gene). PI is converted to PIP: vin sequential phosphorylation (PI kinase ami PIP kinase). Ca" -ATPase Ca:" store SMC Taková rychlost? PDE jeden z nejvýkonnějších známých enzymů Výkonnost transdukce omezena difuzním pohybem v membráně. , OliIlt ttjymi-ní lvII nii-niliMiu- Figur? 13.14 PhototransductJon cJůspé carton channels In the outer segment of ihe phoiorettrpiur membrane In the ddrk, -he tdtiun channels are kept gpen by intraceMy la-r cGMP and conduct an Inward í Uŕíčnt. tarried h t qüäy by Na". WIhín light Stfiktil the- phůturťťůplni, these channels are dosed by 3 G protein-coupled mechanistRO Rhoilopsui inolťcujlť* in Irin di\c rnpmhriine dbsarb light and are atti- vaTed.OThe activated rhodop&iA stErftulaiuS A G prúleln [trdnídnein in rodsk which in Turn actWŕireí cGh/LP pho^phodip^tťr.n^fr 6 Tľie phosphodiesterase t did lyže b the bredJtdowu of cGMP Id S" G MP. O As che cGMP concentration decreases, cGMP detaches n/am rhe cation channel which clüie. 544044 Difúzni model signálového přenosu x Signalplex, scaffolding proteins Rhodopsin \ NI N AC ■t« Wi »•••»• ...... l>Vl > * * Cytoskeletal core b PDZ5 Disulphide bond Reduced Oxidized Organizace signálních proteinů v čase a prostoru - oddělení, zhášení V odpověď na světlo Figure 11 Phototransduction in Drosophila and the I NAD complex, a, The five PDZ domains of INAD (1-5) assemble components of the phototransduction cascade, including PLC, the TRP channel and PKC, into a signalling complex at the cell membrane, b, Mishra et al? report that, in response to light, the PDZ5 domain of INAD undergoes a conformational change. In the dark, PDZ5 is in its canonical, reduced form, in which a groove between an a-helix and a ß-sheet serves as a ligand-binding site. After stimulation with light, the PDZ5 domain undergoes a conformational change to an oxidized state, whereby the formation of a disulphide bond between two cysteine residues results in the unravelling of the a-helix and the distortion of the ligand-binding groove. Following this conformational switch, the ligand (arrowed) — putatively part of the PLC enzyme — can no longer bind. (Adapted from ref. 2.) Taková adaptace? Translokace TRP -Mechanismus adaptace na tmu a světlo insight review articles | Konzervativní organizace 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 '■snake' diagram showing the amino adds fcr a particular receptor (M71 )r 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 extracel lular I oops. b, A schematic vi ew of the proposed three-dimensional structure of the receptor based on the recently solved structure of rhodopsln. Each of the transmembrane regions Is numbered according to that model. The conserved (blue) and variable [reo] regions are sketched onto this qualitative view and suggest that a llgand-blndlng region may be at least partially formed by the variable regions of the receptor. cr Mammalian odour receptors are related phylogenetlca lly to other chemosensory receptors. In the tree depicted here the numbers refer to the approximate number of receptors In each family. ORr Odorant receptors: T1 R, T2H taste receptors; V3Rr vomeronsal receptors; D0Rr DGRr DfusophXa odour and gustatory receptors; worm refers to C. efegans. The scale bar Is a graphical distance equal to 10% sequence divergence. But this ambitious experimental programme has barely progressed, owing to the puzz] ing d ifficulty of expressing ORs i n heterol- release that was measured by fura-Z imaging. Finally, Bird OR-/? TI Rs -80 V2Rs~10O VIRs-150 Á DOR 61 DGR-GO M i—1 H 1 \ Worm OR •■1,000 M______ rf Other GPCRs -400 in marnrnal SENSORY PROCESSES 385 Olfactory neuron til i n of olfactory neuron Figure 13.36 Olfactory transduction mechanisms in cilia membranes of olfactory neurons (a) Many odorants act to increase cyclic AMRThe odorant binds to an odorant receptor on the ciliary membrane; the receptor activates a G protein to activate adenyJyt cyclase, producing cAMP. Cyclic AMP binds to and opens a cation channel, allowing entry of Na1 and Ca2" ions to depolarize the cell. Ca2 ' binds to Ca2+-actívated Cľ channels, augmenting the depolarization, (h) Some olfactory responses increase IP3.~nhis mechanism also starts with odorant binding to a G protein-coupled receptor but in this case the G protein activates phospholipase C forming JP^ from P\?2 (see Figure 12.21).IP3 binds to and opens a calcium channel, fetting Ca~2+ enter to depolarize the ceJt. As in (a), Ca2+-acti-vated CI" channels augment the depolarization. fj?) Increase in cAMP Extracellular fluid Oifactorv. Cffiumof rěcePtoM, olífli ^Odorant molecule Adenylyl Cation . Ga2+-activated cyclase chanriel\ , CI" channel Cytoplasm NTa+ (h) Increase in \P3 Extracellular fluid Olfactory .Odorant olfactory, Calcium K chaiinel C d-"^activated Cl~ channel UMt" 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 increase the surface area of the epithelium; they are covered with the thin 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. c, Wiring of the early olfactory system. Each OSN expresses only one of the -1,000 OR genes and the axons from all cells expressing that particular receptor converge onto one or a few 'glomerulir in the OB. The nearly 2,000 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 OB, 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 interneurons: periglomerular cells and 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 Taste bud SENSORY PROCESSES 383 UV Salt Extracellular fluid m& 'Feiste bud cell membrane m Amiloride-sensitive -cation c ha mi e I—. fbj Sour © <©1 Closed *T ; channel (c) Sweet Receptor i€M$ Depolarization Depol a ri variím asm A deny tyl cyclase f Closed IC channd / G protein cAMF- Depolarization f á) Umami Réospto^ /Glutamate (c) Bitter Closed K+ channel f Bitter substance G protein Decrease in ___ Increase Depolarization cAMP in Ca2' Increased transmitter ívlr.j.- ■ Endoplasmic reticulum Ca2^ igure 13*34 Taste-transduction mechanisms differ for different ste qualities AH transduction mechanisms except the IP3 action in .Mead to depolarization, which spreads to the basal end of the cell nd opens voltage-gated Ca2"1' channels to allow Ca2" entry and transfer release, (a) For salt taste, sodium Ions enter a taste bud cell rough amiloride-sensitive cation channels, directly depolarizing the , (b) In sour taste, either H4" ions enter the cell through amiloride-nsitive cation channels, or they close K+ channels to produce deportation, (c) 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 AMR Cyclic AMP then acti-tes protein kinase A {PKA) to close a K" channel fby phosphorylating it), producing depolarization, (d) The 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 (PDEJ 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 phosphoJi-pase C to produce IP3, IP3 liberates Ca2+ ions from intracellular stores, eliciting transmitter release without requiring depolarization.Other bitter substances bind to (£* channels and close them to depotarize the cell. Salty Sour Urnami Bitter Trehalose Predicted sweet Sweet receptor, (L-glutarnate) (sweet) receptor functional as heterodimer a Y N N N____________ ENaC/Degr ENaCp ASICP Taste mGluR4r T2R family, Predicted receptor T1R3 {sac locus) T1R2/T1R3 others HC N, others others others o\ Drosophita (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 Transduction channel Gating spring Adaptation motor Bundle Climbing + adaptation | Slipping adaptation Box 2 Figure Hair-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 Ca24 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 ; Foot anil mouth — an a r g u mentforana tg e s ics. í bolesti "^ . Figure 2 Polymodat nociceptors use a greater diversity of signal-transduction mechanisms to detect physiological stimuli than do primary sensory neurons in other systems. af In mammals, tight 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 stud ies suggest ttiat TRP -channel family members (VR1 and VRL-1) detect noxious heat, and ttiat 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 ^ ^ ^ Odorants =>('D+ + «A)s <=> {«D* + 'A)T / Formation Singlet of radical Products pair I] <} Photo-transduction Triplet Products v Competing Process Figure 1. Alignment of an earth-strength magnetic field can alter the reaction products of a biochemical reaction that forms radical pair intermediates (Ritz et al. 2000). MP štěpí tripletní stavy a mění pravděpodobnost přeskoků intenzita MP Sever by se mohl stát „viditelný" B/ B/ b trorecepce Afriutctit FltfTintd c*li Rtc«f*or Cafe CapsiieWall Aftafwt Nofti »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 1. Rozmístění Lorenzínlho ampul na těle rejnoka druhu Raja faevis. V levé polovině obrázku je znázorněna dorzální, v pravé polovině pak ventrální scrana těla+ Vpravo nahoře je deiail izolované ampuly; dobře jsou viditelné receptorové buňky na dně ampuly a senzorický nerv+ Podle: Raschi, J, MorphoL 189, 225-247r 19S6, Eye Facial nerve Laíaral I ne ^- canal (a) Cliifttftrí of ampullae Dor*a I branch Posterior laicral line- nervů Gill sins Dram. Current path Command center is| < i..;.- junctions ass u r maximizing signal pling of rhc moduli tor thai d^UTriihitrsI of elecr/rocyteri Cápal A few species, ■ pruducc discharges. I bod i es ? whereas iri ran^c rn m i tli volts tej Or kil] prey, wIictlü! for electro location ; ' Som*; animals Tonic ampul la ry electroreccptor Phasic tuberous Ľlectroreceptor