a genetic screen for dihydropyridine (dhp)-resistant worms reveals new residues required for dhp-blockage of mammalian calcium channels遗传筛查dihydropyridine防(设计马力)蠕虫揭示新的残留dhp-blockage所需的哺乳动物钙通道.pdfVIP

A Genetic Screen for Dihydropyridine (DHP)-Resistant Worms Reveals New Residues Required for DHP- Blockage of Mammalian Calcium Channels 1. 2. 2 1 1 Trevor C. Y. Kwok , Kwokyin Hui , Wojciech Kostelecki , Nicole Ricker , Guillermo Selman , Zhong- 2 1 Ping Feng *, Peter John Roy * 1 Department of Molecular Genetics, The Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada, 2 Department of Physiology, University of Toronto, Toronto, Ontario, Canada Abstract Dihydropyridines (DHPs) are L-type calcium channel (Ca 1) blockers prescribed to treat several diseases including v hypertension. Cav 1 channels normally exist in three states: a resting closed state, an open state that is triggered by membrane depolarization, followed by a non-conducting inactivated state that is triggered by the influx of calcium ions, and a rapid change in voltage. DHP binding is thought to alter the conformation of the channel, possibly by engaging a mechanism similar to voltage dependent inactivation, and locking a calcium ion in the pore, thereby blocking channel conductance. As a Cav 1 channel crystal structure is lacking, the current model of DHP action has largely been achieved by investigating the role of candidate Cav 1 residues in mediating DHP-sensitivity. To better understand DHP-block and identify additional Cav 1 residues important for DHP-sensitivity, we screened 440,000 randomly mutated Caenorhabditis elegans genomes for worms resistant to DHP-induced growth defects. We identified 30 mis