Cav1.3 / Channels / Calcium Ion-Selective / TRANSPORT PROTEIN
機能・相同性
機能・相同性情報
voltage-gated calcium channel activity involved SA node cell action potential / positive regulation of high voltage-gated calcium channel activity / voltage-gated calcium channel activity involved in cardiac muscle cell action potential / positive regulation of adenylate cyclase activity / Presynaptic depolarization and calcium channel opening / regulation of membrane repolarization during action potential / membrane depolarization during SA node cell action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of atrial cardiac muscle cell membrane repolarization / high voltage-gated calcium channel activity ...voltage-gated calcium channel activity involved SA node cell action potential / positive regulation of high voltage-gated calcium channel activity / voltage-gated calcium channel activity involved in cardiac muscle cell action potential / positive regulation of adenylate cyclase activity / Presynaptic depolarization and calcium channel opening / regulation of membrane repolarization during action potential / membrane depolarization during SA node cell action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of atrial cardiac muscle cell membrane repolarization / high voltage-gated calcium channel activity / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / membrane depolarization during cardiac muscle cell action potential / NCAM1 interactions / calcium ion import / regulation of ventricular cardiac muscle cell membrane repolarization / positive regulation of calcium ion transport / cardiac muscle cell action potential involved in contraction / calcium ion transport into cytosol / regulation of potassium ion transmembrane transport / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / ankyrin binding / Sensory processing of sound by inner hair cells of the cochlea / voltage-gated calcium channel complex / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / regulation of calcium ion transport / alpha-actinin binding / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / neuronal dense core vesicle / voltage-gated calcium channel activity / presynaptic active zone membrane / sarcoplasmic reticulum / protein localization to plasma membrane / calcium channel regulator activity / Regulation of insulin secretion / sensory perception of sound / GABA-ergic synapse / calcium ion transmembrane transport / calcium channel activity / Z disc / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cellular response to amyloid-beta / calcium ion transport / Adrenaline,noradrenaline inhibits insulin secretion / T cell receptor signaling pathway / chemical synaptic transmission / synapse / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol 類似検索 - 分子機能
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
5R01GM130762
米国
引用
ジャーナル: Cell / 年: 2022 タイトル: Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca channels. 著者: Xia Yao / Shuai Gao / Jixin Wang / Zhangqiang Li / Jian Huang / Yan Wang / Zhifei Wang / Jiaofeng Chen / Xiao Fan / Weipeng Wang / Xueqin Jin / Xiaojing Pan / Yong Yu / Armando Lagrutta / Nieng Yan / 要旨: Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate ...Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Ca channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca1.1 and Ca1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Ca channels.