voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of muscle contraction / positive regulation of high voltage-gated calcium channel activity / membrane depolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during AV node cell action potential ...voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of muscle contraction / positive regulation of high voltage-gated calcium channel activity / membrane depolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / photoreceptor ribbon synapse / positive regulation of calcium ion transport / cardiac muscle cell action potential involved in contraction / calcium ion import / regulation of ventricular cardiac muscle cell membrane repolarization / NCAM1 interactions / Sensory processing of sound by inner hair cells of the cochlea / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / neuromuscular junction development / Phase 0 - rapid depolarisation / neuronal dense core vesicle / regulation of heart rate by cardiac conduction / regulation of calcium ion transport / calcium ion import across plasma membrane / voltage-gated calcium channel activity / T-tubule / visual perception / sarcoplasmic reticulum / Regulation of insulin secretion / protein localization to plasma membrane / calcium ion transmembrane transport / postsynaptic density membrane / calcium channel activity / Adrenaline,noradrenaline inhibits insulin secretion / cellular response to amyloid-beta / calcium ion transport / actin filament binding / presynapse / chemical synaptic transmission / perikaryon / dendrite / extracellular exosome / metal ion binding / plasma membrane 類似検索 - 分子機能
ジャーナル: Nat Commun / 年: 2024 タイトル: Structural bases of inhibitory mechanism of Ca1.2 channel inhibitors. 著者: Yiqing Wei / Zhuoya Yu / Lili Wang / Xiaojing Li / Na Li / Qinru Bai / Yuhang Wang / Renjie Li / Yufei Meng / Hao Xu / Xianping Wang / Yanli Dong / Zhuo Huang / Xuejun Cai Zhang / Yan Zhao / 要旨: The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved ...The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6, S6, and S6 helices and forms extensive hydrophobic interactions with Ca1.2. Our structure elucidates that benidipine is located in the D-D fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5, S6, and S6 helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.