Transient receptor potential A1 (TRPA1) is an excitatory ion channel that functions as a cellular sensor, detecting a wide range of proalgesic agents such as environmental irritants and endogenous products of inflammation and oxidative stress. Topical application of TRPA1 agonists produces an acute nociceptive response through peripheral release of neuropeptides, purines and other transmitters from activated sensory nerve endings. This, in turn, further regulates TRPA1 activity downstream of G-protein and phospholipase C-coupled signaling cascades. Despite the important physiological relevance of such regulation leading to nociceptor sensitization and consequent pain hypersensitivity, the specific domains through which TRPA1 undergoes post-translational modifications that affect its activation properties are yet to be determined at a molecular level. This review aims at providing an account of our current knowledge on molecular basis of regulation by neuronal inflammatory signaling pathways that converge on the TRPA1 channel protein and through modification of its specific residues influence the extent to which this channel may contribute to pain.

• MeSH
• bolest genetika   metabolismus   MeSH
• bradykinin genetika   metabolismus   MeSH
• kationtový kanál TRPA1 fyziologie   MeSH
• lidé MeSH
• nociceptory fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Gain-of-function (GOF) mutations in ion channels are rare events, which lead to increased agonist sensitivity or altered gating properties, and may render the channel constitutively active. Uncovering and following characterization of such mutants contribute substantially to the understanding of the molecular basis of ion channel functioning. Here we give an overview of some GOF mutants in polymodal ion channels specifically involved in transduction of painful stimuli--TRPV1 and TRPA1, which are scrutinized by scientists due to their important role in development of some pathological pain states. Remarkably, a substitution of single amino acid in the S4-S5 region of TRPA1 (N855S) has been recently associated with familial episodic pain syndrome. This mutation increases chemical sensitivity of TRPA1, but leaves the voltage sensitivity unchanged. On the other hand, mutations in the analogous region of TRPV1 (R557K and G563S) severely affect all aspects of channel activation and lead to spontaneous activity. Comparison of the effects induced by mutations in homologous positions in different TRP receptors (or more generally in other distantly related ion channels) may elucidate the gating mechanisms conserved during evolution.

• MeSH
• bolest patofyziologie   MeSH
• kationtové kanály TRP chemie   genetika   metabolismus   MeSH
• kationtové kanály TRPV chemie   genetika   metabolismus   MeSH
• lidé MeSH
• mícha patofyziologie   MeSH
• mutace genetika   MeSH
• percepce bolesti MeSH
• proteiny nervové tkáně chemie   genetika   metabolismus   MeSH
• vápníkové kanály chemie   genetika   metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The ankyrin transient receptor potential channel TRPA1 is a non-selective cationic channel that is expressed by sensory neurons, where it can be activated by pungent chemicals, such as AITC (allyl isothiocyanate), cinnamon or allicin, by deep cooling (<18 °C) or highly depolarizing voltages (>+100 mV). From the cytoplasmic side, this channel can be regulated by negatively charged ligands such as phosphoinositides or inorganic polyphosphates, most likely through an interaction with as yet unidentified positively charged domain(s). In the present study, we mutated 27 basic residues along the C-terminal tail of TRPA1, trying to explore their role in AITC- and voltage-dependent gating. In the proximal part of the C-terminus, the function-affecting mutations were at Lys969, Arg975, Lys988 and Lys989. A second significant region was found in the predicted helix, centred around Lys1048 and Lys1052, in which single alanine mutations completely abolished AITC- and voltage-dependent activation. In the distal portion of the C-terminus, the charge neutralizations K1092A and R1099A reduced the AITC sensitivity, and, in the latter mutant, increased the voltage-induced steady-state responses. Taken together, our findings identify basic residues in the C-terminus that are strongly involved in TRPA1 voltage and chemical sensitivity, and some of them may represent possible interaction sites for negatively charged molecules that are generally considered to modulate TRPA1.

• MeSH
• aminokyseliny bazické genetika   fyziologie   MeSH
• ankyrinová repetice MeSH
• ankyriny MeSH
• ionty farmakologie   MeSH
• kationtové kanály TRP chemie   metabolismus   MeSH
• lidé MeSH
• membránové potenciály fyziologie   MeSH
• nervové receptory chemie   MeSH
• proteiny nervové tkáně chemie   metabolismus   MeSH
• statická elektřina MeSH
• substituce aminokyselin MeSH
• vápníkové kanály chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ankyrinový receptor typu 1 (TRPAl) je iontový kanál, jehož funkce se uplatňuje v přenosu bolestivých podnětů na primárních nociceptivních neuronech. Tento z nichž mnohé zprostředkovávají senzorické vjemy přicházející z okolního prostředí: algogenní, pálivé nebo chladivé látky nacházející se v různých rostlinách, bolestivé teplo nebo chlad. TRPAl kanál lze aktivovat řadou dráždivých látek, organosulfátů, obsažených v hořčici, křenu, česneku nebo cibuli, dráždivými aldehydy nacházejícími se ve výfukových a slzných plynech nebo v cigaretovém kouři. Tento iontový kanál je ale také )římo aktivován chladem, mediatory zánětu, endogenními produkty oxidativního stresu a překvapivě i psychoaktivními látkami, jako jsou fytokanabinoidy. Cílem tohoto příspěvku je informovat o současných poznatcích týkajících se strukturálních, funkčních a farmakologických vlastností TRPAl receptoru, zejména z hlediska možného fyziologického významu a případných souvislostí s periferními mechanizmy nocicepce, které byly v uplynulých letech studovány na oddělení buněčné neurofyziologie Fyziologického ústavu AV CR, v.v.i. (http.7/www2.biomed.cas. cz/d331/index.htm).

The ankyrin transient receptor potential subtype 1 (TRPA1) is an ion channel that is highly expressed in primary sensory neuron s with noci- ceptive properties. This channel belongs to a diverse collection of membrane proteins: transient receptor potential (TRP) chann el superfamily, some members of which mediate a variety of sensory qualities that are clearly related to pain: stinging, pricking, warmth, burn ing or cold. The TRPA1 channel can be activated by some organosulfur compounds contained in mustard oil, horse radish or garlic, environmental i rritants contained in air polution, cigarette smoke or tear gas, by cold, inflammatory mediators and, interestingly, also by some psycho active drugs such as phytocannabinoids. The purpose of this article is to give an overview of the pharmacological, structural and functional prop erties of the TRPA1 receptor with a focus on its potential physiological role in peripheral mechanisms of nociception that have been studied at the Department of Cellular Neurophysiology of the Institute of Physiology AS CR, v.v.i. (http://www2.biomed.cas.cz/d331/index_eng.htm).

• Klíčová slova
• ankyrinový receptor, chlad, termo-TRP receptory, ganglia zadních kořenů míšních, senzorická transdukce,
• MeSH
• bolest MeSH
• financování organizované MeSH
• gating iontového kanálu fyziologie   MeSH
• hyperalgezie metabolismus   MeSH
• kanabinoidy farmakologie   metabolismus   MeSH
• kationtové kanály TRP agonisté   antagonisté a inhibitory   fyziologie   MeSH
• modely u zvířat MeSH
• neurony metabolismus   MeSH
• nocicepce MeSH
• nociceptory fyziologie   metabolismus   účinky léků   MeSH
• psychotropní léky farmakologie   metabolismus   MeSH

The past decade has seen a progressive unraveling of the molecular identities of receptors implicated in transduction of painful stimuli. Among the line-up of important ion channels involved in peripheral pain pathways, the family of the transient receptor potential (TRP) ion channels has attracted considerable attention and research work as a target class for drug discovery. One of these channels, the ankyrin transient receptor potential TRPA1, which expression is restricted to nociceptive neurons of peripheral ganglia, can be activated by isothiocyanates, pungent products from mustard oil and horse radish, phytocannabinoids, nicotin, environmental irritants contained in air polution, cigarette smoke and tear gas, but also by inflammatory mediators and endogenous products of oxidative stress. The purpose of this paper is to give an overview of the pharmacological, structural and functional properties of the TRPA1 channel in mammalian sensory system and to summarize recent evidence regarding its key properties that can be exploited for potential therapeutic advantage.

• Klíčová slova
• ankyrinový receptor, chlad, enzorická transdukce,
• MeSH
• ankyriny fyziologie   genetika   MeSH
• bolest MeSH
• financování organizované MeSH
• hyperalgezie etiologie   farmakoterapie   MeSH
• kationtové kanály TRP fyziologie   chemie   MeSH
• nocicepce MeSH
• nociceptory fyziologie   účinky léků   MeSH
• receptory Notch fyziologie   chemie   metabolismus   MeSH
• Publikační typ
• přehledy MeSH