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10.1074/jbc.M200448200 http://scihub22266oqcxt.onion/10.1074/jbc.M200448200 11960982!ä!11960982 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Biol+Chem 2002 ; 277 (26): 23587-95 Nephropedia Template TP {{tp|p=11960982|t=2002. Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block |pdf=|usr=}}{{11960982}} gab.com Text Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=11960982 #FOAvip The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K(+) channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC(50) was 8.4 +/- 0.9 microm when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC(50) > 1 mm at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at +40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together these findings indicate a critical role for Tyr-652 in voltage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cation-pi and pi-stacking interactions with Tyr-652 and Phe-656 of multiple subunits. Twit Text FOAVip Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=11960982 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=11960982 #FOAvip English Wikipedia <ref>{{Cite pmid|11960982}}</ref> Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block #MMPMID11960982 Sanchez-Chapula JA; Navarro-Polanco RA; Culberson C; Chen J; Sanguinetti MC J Biol Chem 2002[Jun]; 277 (26): 23587-95 PMID11960982show ga The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K(+) channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC(50) was 8.4 +/- 0.9 microm when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC(50) > 1 mm at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at +40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together these findings indicate a critical role for Tyr-652 in voltage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cation-pi and pi-stacking interactions with Tyr-652 and Phe-656 of multiple subunits. |*Cation Transport Proteins[MESH] |*DNA-Binding Proteins[MESH] |*Potassium Channel Blockers[MESH] |*Potassium Channels, Voltage-Gated[MESH] |*Trans-Activators[MESH] |Benzopyrans/pharmacology[MESH] |Binding Sites[MESH] |Chloroquine/pharmacology[MESH] |ERG1 Potassium Channel[MESH] |Ether-A-Go-Go Potassium Channels[MESH] |Humans[MESH] |Membrane Potentials[MESH] |Piperidines/pharmacology[MESH] |Potassium Channels/chemistry/physiology[MESH] |Structure-Activity Relationship[MESH]Molecular determinants of voltage-dependent human ether-a-go-go relate(epmc).pdf DeepDyve Pubget Overpricing