Q112424409
Dotaz
Zobrazit nápovědu
- Klíčová slova
- extracelulární ATP,
- MeSH
- adenosintrifosfát fyziologie MeSH
- chronická bolest etiologie MeSH
- extracelulární prostor MeSH
- lidé MeSH
- mikroglie MeSH
- nervový přenos * fyziologie MeSH
- neuralgie * etiologie MeSH
- poranění periferního nervu MeSH
- purinergní receptory P2X * fyziologie MeSH
- purinergní receptory P2X3 fyziologie MeSH
- purinergní receptory P2X4 fyziologie MeSH
- purinergní receptory P2X7 fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Ivermectin acts as a positive allosteric regulator of several ligand-gated channels including the glutamate-gated chloride channel (GluCl), gamma aminobutyric acid type-A receptor, glycine receptor, neuronal alpha7-nicotinic receptor and purinergic P2X4 receptor. In most of the ivermectin-sensitive channels, the effects of ivermectin include the potentiation of agonist-induced currents at low concentrations and channel opening at higher concentrations. Based on mutagenesis, electrophysiological recordings and functional analysis of chimeras between ivermectin-sensitive and ivermectin-insensitive receptors, it has been concluded that ivermectin acts by insertion between transmembrane helices. The three-dimensional structure of C. elegans GluCl complexed with ivermectin has revealed the details of the ivermectin-binding site, however, no generic motif of amino acids could accurately predict ivermectin binding site for other ligand gated channels. Here, we will review what is currently known about ivermectin binding and modulation of Cys-loop receptor family of ligand-gated ion channels and what are the critical structural determinants underlying potentiation of the P2X4 receptor channel.
- MeSH
- alosterická regulace MeSH
- alosterické místo MeSH
- biologické modely MeSH
- chemické modely MeSH
- gating iontového kanálu * MeSH
- iontové kanály chemie metabolismus ultrastruktura MeSH
- ivermektin chemie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Purinergic P2X receptors (P2XR), activated by extracellular adenosine 5‘-triphosphate (ATP), represent a specific type of li- gand-gated ion channels. They form functional trimeric homomers or heteromers which are nonselectively cation-perme- able after receptor activation. P2X receptors are widely expressed in excitable and nonexcitable tissues and are involved in many physiological and pathophysiological processes such as platelet aggregation, contraction of smooth muscle, immu- ne responses, cell proliferation and apoptosis or neurotransmission. In mammals, seven P2X subunits (P2X1-P2X7) have been identified. They differ mainly in distribution, pharmacological profile and kinetics of ATP-induced responses. The sub- type P2X7 is the most specific in the P2X family and widely differs from other P2X subtypes.
- Klíčová slova
- extracelulární ATP, purinergní P2X rodina, buněčná proliferace a apoptóza,
- MeSH
- adenosintrifosfát biosyntéza MeSH
- agonisté purinergního receptoru P2X farmakokinetika farmakologie MeSH
- apoptóza fyziologie MeSH
- extracelulární prostor MeSH
- fyziologie buňky MeSH
- lidé MeSH
- mezibuněčné signální peptidy a proteiny MeSH
- proliferace buněk MeSH
- purinergní receptory P2X * analýza biosyntéza fyziologie izolace a purifikace klasifikace metabolismus účinky léků MeSH
- purinergní receptory P2X1 krev MeSH
- purinergní receptory P2X3 fyziologie MeSH
- purinergní receptory P2X4 MeSH
- purinergní receptory P2X7 imunologie MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Mammalian P2X receptors contain 10 conserved cysteine residues in their ectodomains, which form five disulfide bonds (SS1-5). Here, we analyzed the relevance of these disulfide pairs in rat P2X4 receptor function by replacing one or both cysteines with alanine or threonine, expressing receptors in HEK293 cells and studying their responsiveness to ATP in the absence and presence of ivermectin, an allostenic modulator of these channels. Response to ATP was not altered when both cysteines forming the SS3 bond (C132-C159) were replaced with threonines. Replacement of SS1 (C116-C165), SS2 (C126-C149) and SS4 (C217-C227), but not SS5 (C261-C270), cysteine pairs with threonines resulted in decreased sensitivity to ATP and faster deactivation times. The maximum current amplitude was reduced in SS2, SS4 and SS5 double mutants and could be partially rescued by ivermectin in SS2 and SS5 double mutants. This response pattern was also observed in numerous single residue mutants, but receptor function was not affected when the 217 cysteine was replaced with threonine or arginine or when the 261 cysteine was replaced with alanine. These results suggest that the SS1, SS2 and SS4 bonds contribute substantially to the structure of the ligand binding pocket, while the SS5 bond located towards the transmembrane domain contributes to receptor gating.
- MeSH
- cystein genetika chemie MeSH
- financování organizované MeSH
- gating iontového kanálu fyziologie MeSH
- HEK293 buňky MeSH
- konzervovaná sekvence MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- purinergní receptory P2X4 genetika chemie metabolismus MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
