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 / Presynaptic depolarization and calcium channel opening / regulation of membrane repolarization during action potential / membrane depolarization during atrial cardiac muscle cell action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / Phase 2 - plateau phase / photoreceptor ribbon synapse / signaling / cell communication ...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 / Presynaptic depolarization and calcium channel opening / regulation of membrane repolarization during action potential / membrane depolarization during atrial cardiac muscle cell action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / Phase 2 - plateau phase / photoreceptor ribbon synapse / signaling / cell communication / membrane depolarization during AV node cell action potential / L-type voltage-gated calcium channel complex / calcium ion transport into cytosol / membrane depolarization during bundle of His cell action potential / positive regulation of muscle contraction / calcium ion import / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization / positive regulation of calcium ion transport / cardiac muscle cell action potential involved in contraction / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of heart contraction / voltage-gated calcium channel complex / Sensory processing of sound by inner hair cells of the cochlea / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / calcium ion transmembrane import into cytosol / regulation of calcium ion transport / Phase 0 - rapid depolarisation / neuromuscular junction development / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / neuronal dense core vesicle / voltage-gated calcium channel activity / muscle contraction / presynaptic active zone membrane / T-tubule / protein localization to plasma membrane / positive regulation of insulin secretion involved in cellular response to glucose stimulus / sarcoplasmic reticulum / Regulation of insulin secretion / regulation of membrane potential / postsynaptic density membrane / GABA-ergic synapse / cellular response to amyloid-beta / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / actin filament binding / Adrenaline,noradrenaline inhibits insulin secretion / presynapse / chemical synaptic transmission / perikaryon / calmodulin binding / 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.