Article
Neurosciences
Jing Xue, Yan Han, Weizhong Zeng, Yan Wang, Youxing Jiang
Summary: This study reveals the structural mechanism of ligand gating in the human rod CNGA1 channel, including channel conformation and ion binding sites, providing insights into Ca2+ blockage and permeation in CNG channels.
Article
Pharmacology & Pharmacy
Paulo Pinares-Garcia, James Spyrou, Chaseley E. McKenzie, Ian C. Forster, Ming S. Soh, Erlina Mohamed Syazwan, Mohammed Atif, Christopher A. Reid
Summary: In this study, the effects of Org 34167 on HCN channels were analyzed in human embryonic kidney cells and mouse neurons. The results showed that Org 34167 is a broad-spectrum inhibitor of HCN channels, slowing activation and causing a hyperpolarising shift in voltage-dependence of activation. It also reduced I (h)-mediated sag in mouse neurons. Additionally, Org 34167 exhibited anti-depressive activity in mice, but higher doses resulted in adverse effects.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biology
Joseph L. Ransdell, Jonathan D. Moreno, Druv Bhagavan, Jonathan R. Silva, Jeanne M. Nerbonne
Summary: The resurgent component of the voltage-gated sodium current (I-NaR) is a depolarizing conductance that regulates the firing properties of various neuronal cell types. The mechanism behind the generation of I-NaR, mediated by voltage-gated sodium channels, remains unclear. This study provides evidence that resurgent Na+ influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and the decay of I-NaR reflects the slow accumulation of recovered/opened Nav channels into a second inactivated state. The amplitude of I-NaR can be modulated by factors such as the accessory Nav beta 4 channel subunit.
Article
Multidisciplinary Sciences
Aaron P. Owji, Jiali Wang, Alec Kittredge, Zada Clark, Yu Zhang, Wayne A. Hendrickson, Tingting Yang
Summary: This study reports the cryo-EM structures of human Bestrophin, revealing the molecular mechanisms of its function. The C-terminal auto-inhibitory segment plays a crucial role in regulating the opening of the channel, highlighting the significance of this finding in understanding the functions of the Bestrophin family.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Wenlei Ye, Hongtu Zhao, Yaxin Dai, Yingdi Wang, Yu-hua Lo, Lily Yeh Jan, Chia-Hsueh Lee
Summary: This article reports the structures of the K(V)4 channel in inactivated, open, and closed states, elucidating the mechanisms of inactivation and voltage-dependent activation, particularly the mechanism of closed-state inactivation. The findings contribute to a better understanding of the functional regulation of ion channels.
Article
Chemistry, Medicinal
Marius Patberg, Tengiz Oniani, Paul Disse, Stefan Peischard, Laura Vinnenberg, Mehrnoush Zobeiri, Maria N. Romanelli, Lisa Epping, Heinz Wiendl, Sven G. Meuth, Petra Hundehege, Guiscard Seebohm, Thomas Budde, Anna Junker
Summary: HCN4 channels are potential targets for treating cardiac pathologies, epilepsy, and multiple sclerosis. However, there is a lack of subtype-selective HCN channel blockers. This study reports the synthesis of EC18 and its evaluation in various pharmacological models to assess its effects on cardiac function, thalamocortical neurons, and immune cells.
ARCHIV DER PHARMAZIE
(2023)
Article
Geochemistry & Geophysics
Hongran Chen, Chao Xu, Yuan Cui, Siqing Qin
Summary: Locked segment-dominated landslides occur when locked segments are sufficiently damaged to be unlocked. The displacement pattern in the evolution towards instability is governed by mechanical synergy between the ruptured locked segment and the transfixion segment. The brittleness of locked segments determines the rapid or slow resistance homogenization, leading to two unlocking-induced startup mechanisms and one of the two displacement patterns. External factors, like rainwater, can affect the strength of geomaterials but not the inherent mechanical rules followed by locked segments.
Editorial Material
Biochemistry & Molecular Biology
Vanessa J. Flegler, Tim Rasmussen, Bettina Boettcher
Summary: The bacterial mechanosensitive channel of small conductance (MscS) enters a desensitized state when it loses all coordinated lipids under membrane tension, as visualized in a recent study by Zhang et al.
TRENDS IN BIOCHEMICAL SCIENCES
(2021)
Article
Cell Biology
Xiaofei Wang, Yawen Li, Hong Wei, Zhisen Yang, Rui Luo, Yongxiang Gao, Wei Zhang, Xin Liu, Linfeng Sun
Summary: TRPA1 is an ion channel that responds to noxious temperature or chemical stimuli. The thermosensitivity of TRPA1 varies among different species or isoforms. This study determines the structures of a heat-sensitive isoform of TRPA1 in fruit flies and identifies conformational changes in the ankyrin repeat domain and coiled-coil domain. The findings provide insights into the gating mechanism of TRPA1.
Review
Biochemistry & Molecular Biology
Gregorio Fernandez-Ballester, Asia Fernandez-Carvajal, Antonio Ferrer-Montiel
Summary: The thermoTRP family of ion channels, which includes multiple nonselective cation channels, are activated by physical and chemical stimuli, functioning as polymodal receptors. These channels undergo gating through changes in temperature, osmolarity, voltage, pH, pressure, and by chemical compounds that bind to the proteins. Recent advances in cryo-electron microscopy techniques have provided high-resolution structures of these channels in different states, shedding light on the underlying allosteric gating mechanisms. Understanding these mechanisms is important for the development of drug-based therapies for diseases involving dysfunctional thermoTRP channels, such as chronic pain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Jing Xue, Yan Han, Weizhong Zeng, Youxing Jiang
Summary: Mammalian cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cGMP or cAMP and play essential roles in signal transduction. The rod CNG channels exist as heterotetramers with different functional properties compared to the homotetrameric CNGA1 model system. The functional analysis and cryo-EM structures of the human rod CNGA1/B1 heterotetramer provide insights into its subunit stoichiometry, gating mechanism, and pharmacological characteristics.
Article
Cell Biology
Jiangtao Zhang, Shiqi Liu, Junping Fan, Rui Yan, Bo Huang, Feng Zhou, Tian Yuan, Jianke Gong, Zhu Huang, Daohua Jiang
Summary: In this study, cryoelectron microscopy was used to obtain structures of the Slo2.2 channel in closed, open, and inhibitor-bound form, providing insights into its cation regulation and inhibition. The closed state of Slo2.2 contains multiple K+ and Zn2+ binding sites in the cytoplasmic gating ring domain, which stabilize the closed conformation. The open state reveals Na+-sensitive sites that induce gating ring expansion and rotation upon Na+ binding, leading to inner gate opening. Additionally, a potent inhibitor blocks the pore by binding to a pocket formed by the pore helix and S6 helix. These findings establish a structural framework for studying Slo2.2 channel gating, Na+ sensation, and inhibition.
Article
Multidisciplinary Sciences
Linus J. Conrad, Peter Proks, Stephen J. Tucker
Summary: This passage discusses a voltage-dependent gating process in the TREK-2 K+ channel, which can be modulated by small molecule agonists and high internal K+ concentrations. It is found that high ionic-strength can inhibit the channel conductance, while the activatory effect of BL1249 on channel open probability persists under these conditions. The influence of negatively charged activators like BL1249 on permeation is consistent with an electrostatic mechanism, suggesting complexity in their effect on channel gating.
Article
Cell Biology
Yanli Dong, Yiwei Gao, Shuai Xu, Yuhang Wang, Zhuoya Yu, Yue Li, Bin Li, Tian Yuan, Bei Yang, Xuejun Cai Zhang, Daohua Jiang, Zhuo Huang, Yan Zhao
Summary: This study sheds light on the structure of the human Ca(V)2.2 channel complex, providing insights for developing new state-dependent blockers for the treatment of chronic pain.
Article
Biochemistry & Molecular Biology
Daohua Jiang, Richard Banh, Tamer M. Gamal El-Din, Lige Tonggu, Michael J. Lenaeus, Regis Pomes, Ning Zheng, William A. Catterall
Summary: Research has uncovered the open-state structure of the sodium channel Na(v)1.5, revealing the mechanism of pore opening by blocking fast inactivation. This provides crucial molecular-level insights into the initiation of heartbeat.
