FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2959781137> ?p ?o ?g. }

• W2959781137 abstract "TASK channels are unusual members of the two-pore domain potassium (K 2P ) channel family, with unique and unexplained physiological and pharmacological characteristics. TASKs are found in neurons 1,2 , cardiomyocytes 3–5 and vascular smooth muscle cells 6 where they are involved in regulation of heart rate 7 , pulmonary artery tone 6,8 , sleep/wake cycles 9 and responses to volatile anaesthetics 9–12 . K 2P channels regulate the resting membrane potential, providing background K + currents controlled by numerous physiological stimuli 13,14 . Unlike other K 2P channels, TASK channels have the capacity to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. These characteristics make the TASK channels some of the the most easily druggable potassium channels, and indeed TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnea (OSA) and atrial fibrillation (Afib) 15 (The DOCTOS and SANDMAN Trials). Generally, potassium channels have an intramembrane vestibule with a selectivity filter above and a gate with four parallel helices below. However, K 2P channels studied to date all lack a lower gate. Here we present the structure of TASK-1, revealing a unique lower gate created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance, which we designate as an ‟X-gate”. This structure is formed by six residues (V 243 LRFMT 248 ) that are essential for responses to volatile anaesthetics 11 , neuro-transmitters 16 and G-protein coupled receptors 16 . Interestingly, mutations within the X-gate and surrounding regions drastically affect both open probability and activation by anaesthetics. Structures of TASK-1 with two novel, high-affinity blockers, shows both inhibitors bound below the selectivity filter, trapped in the vestibule by the X-gate, thus explaining their exceptionally low wash-out rates. Thus, the presence of the X-gate in TASK channels explains many aspects of their unusual physiological and pharmacological behaviour, which is invaluable for future development and optimization of TASK modulators for treatment of heart, lung and sleep disorders." @default.
• W2959781137 created "2019-07-23" @default.
• W2959781137 creator A5006725137 @default.
• W2959781137 creator A5008574547 @default.
• W2959781137 creator A5009272032 @default.
• W2959781137 creator A5015037677 @default.
• W2959781137 creator A5020202026 @default.
• W2959781137 creator A5020206515 @default.
• W2959781137 creator A5030290228 @default.
• W2959781137 creator A5037999983 @default.
• W2959781137 creator A5044551482 @default.
• W2959781137 creator A5057174416 @default.
• W2959781137 creator A5057457480 @default.
• W2959781137 creator A5058775657 @default.
• W2959781137 creator A5059258565 @default.
• W2959781137 creator A5069686330 @default.
• W2959781137 creator A5073016714 @default.
• W2959781137 creator A5074758586 @default.
• W2959781137 creator A5084053909 @default.
• W2959781137 creator A5087017698 @default.
• W2959781137 creator A5088882821 @default.
• W2959781137 creator A5089871276 @default.
• W2959781137 date "2019-07-19" @default.
• W2959781137 modified "2023-10-13" @default.
• W2959781137 title "A unique lower X-gate in TASK channels traps inhibitors within the vestibule" @default.
• W2959781137 cites W135965306 @default.
• W2959781137 cites W1541419413 @default.
• W2959781137 cites W1613705179 @default.
• W2959781137 cites W1798638058 @default.
• W2959781137 cites W1850125528 @default.
• W2959781137 cites W1905155416 @default.
• W2959781137 cites W1908670897 @default.
• W2959781137 cites W1963631121 @default.
• W2959781137 cites W1974841606 @default.
• W2959781137 cites W1980779109 @default.
• W2959781137 cites W1984519311 @default.
• W2959781137 cites W1985417036 @default.
• W2959781137 cites W1989094945 @default.
• W2959781137 cites W1992693738 @default.
• W2959781137 cites W2002574027 @default.
• W2959781137 cites W2006090981 @default.
• W2959781137 cites W2017580134 @default.
• W2959781137 cites W2030922163 @default.
• W2959781137 cites W2032443344 @default.
• W2959781137 cites W2041345208 @default.
• W2959781137 cites W2058930369 @default.
• W2959781137 cites W2079633622 @default.
• W2959781137 cites W2085566501 @default.
• W2959781137 cites W2086569631 @default.
• W2959781137 cites W2095780887 @default.
• W2959781137 cites W2100642038 @default.
• W2959781137 cites W2108921801 @default.
• W2959781137 cites W2118033887 @default.
• W2959781137 cites W2119252267 @default.
• W2959781137 cites W2124026197 @default.
• W2959781137 cites W2129533113 @default.
• W2959781137 cites W2131597783 @default.
• W2959781137 cites W2148580810 @default.
• W2959781137 cites W2152195928 @default.
• W2959781137 cites W2155881793 @default.
• W2959781137 cites W2157618404 @default.
• W2959781137 cites W2180229411 @default.
• W2959781137 cites W2238432127 @default.
• W2959781137 cites W2272748871 @default.
• W2959781137 cites W2414227614 @default.
• W2959781137 cites W2615430757 @default.
• W2959781137 cites W2724716579 @default.
• W2959781137 cites W2912685906 @default.
• W2959781137 cites W2913476645 @default.
• W2959781137 cites W2917655929 @default.
• W2959781137 cites W4210675630 @default.
• W2959781137 cites W4248872320 @default.
• W2959781137 doi "https://doi.org/10.1101/706168" @default.
• W2959781137 hasPublicationYear "2019" @default.
• W2959781137 type Work @default.
• W2959781137 sameAs 2959781137 @default.
• W2959781137 citedByCount "3" @default.
• W2959781137 countsByYear W29597811372019 @default.
• W2959781137 countsByYear W29597811372020 @default.
• W2959781137 countsByYear W29597811372021 @default.
• W2959781137 crossrefType "posted-content" @default.
• W2959781137 hasAuthorship W2959781137A5006725137 @default.
• W2959781137 hasAuthorship W2959781137A5008574547 @default.
• W2959781137 hasAuthorship W2959781137A5009272032 @default.
• W2959781137 hasAuthorship W2959781137A5015037677 @default.
• W2959781137 hasAuthorship W2959781137A5020202026 @default.
• W2959781137 hasAuthorship W2959781137A5020206515 @default.
• W2959781137 hasAuthorship W2959781137A5030290228 @default.
• W2959781137 hasAuthorship W2959781137A5037999983 @default.
• W2959781137 hasAuthorship W2959781137A5044551482 @default.
• W2959781137 hasAuthorship W2959781137A5057174416 @default.
• W2959781137 hasAuthorship W2959781137A5057457480 @default.
• W2959781137 hasAuthorship W2959781137A5058775657 @default.
• W2959781137 hasAuthorship W2959781137A5059258565 @default.
• W2959781137 hasAuthorship W2959781137A5069686330 @default.
• W2959781137 hasAuthorship W2959781137A5073016714 @default.
• W2959781137 hasAuthorship W2959781137A5074758586 @default.
• W2959781137 hasAuthorship W2959781137A5084053909 @default.
• W2959781137 hasAuthorship W2959781137A5087017698 @default.
• W2959781137 hasAuthorship W2959781137A5088882821 @default.

• next