Article
Physiology
Young-Woo Nam, Meng Cui, Razan Orfali, Adam Viegas, Misa Nguyen, Eman H. M. Mohammed, Khalid A. Zoghebi, Simin Rahighi, Keykavous Parang, Miao Zhang
Summary: The hydrophobic interactions between the HA helix and the S4-S5 linker are found to be the main determinant of channel apparent Ca(2+) sensitivity in SK2 channels. Mutations that alter the hydrophobicity at this interface can lead to either hypersensitivity or hyposensitivity to Ca2+. This study highlights the crucial role of interactions between the HA helix and S4-S5 linker in regulating the Ca(2+) sensitivity of SK2 channels.
Article
Multidisciplinary Sciences
Robert Oda, Jingwen Shou, Wenying Zhong, Yasuyuki Ozeki, Masato Yasui, Mutsuo Nuriya
Summary: Using SRS microscopy, we directly visualize the interactions of a deuterated analog of propofol in living cells, supporting the theory that propofol primarily interacts with the plasma membrane of neurons through non-specific binding. Additionally, we demonstrate that SRS microscopy can be used to monitor the dynamics of propofol binding in real-time.
Article
Multidisciplinary Sciences
Enqiang Chang, Yangyang Wang, Ruilou Zhu, Lingzhi Wu, Yitian Yang, Shuang Zeng, Ningtao Li, Xiaoguo Ruan, Mingyang Sun, Wei Zhang, Jun Zhou, Mengrong Miao, Hui Zhi, Hailin Zhao, Qian Chen, Qizhe Sun, Emer Chang, Albert Chang, Tingting Zhang, Xinfang He, Kan Liu, Songhua Ma, Weizhong Zhu, Youming Zhang, Luca Magnani, Daqing Ma, Jiaqiang Zhang
Summary: By using single-cell RNA sequencing, whole-cell patch clamp, and calcium transient techniques, we investigated the effects of propofol and sevoflurane on the gene transcriptome and ion channels in human fetal prefrontal cortex cells. Both propofol and sevoflurane promoted microgliosis, but only sevoflurane decreased the transcriptional similarity of microglia. Both anesthetics transiently altered the transcriptome profiling of various cell types, such as microglia, excitatory neurons, interneurons, astrocytes, and oligodendrocyte progenitor cells, for less than 2 hours. Our study provides valuable insights for future mechanistic studies of general anesthetics in clinical settings.
Article
Multidisciplinary Sciences
Jinglei Xiao, Vasyl Bondarenko, Yali Wang, Antonio Suma, Marta Wells, Qiang Chen, Tommy Tillman, Yan Luo, Buwei Yu, William P. Dailey, Roderic Eckenhoff, Pei Tang, Vincenzo Carnevale, Michael L. Klein, Yan Xu
Summary: This study identifies residue T140 in the S4-S5 linker of bacterial sodium channels as critical for channel activation and drug effects on inactivation. The drug propofol binds to a pocket between the S4-S5 linker and S6 helix in a conformation-dependent manner, promoting and stabilizing inactivated states. The results provide direct evidence of distinct interactions between the S4-S5 linker and S6 helix in activated and inactivated states, pointing towards a potential direction for conformation-dependent drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Physical
Vladimir I. Novoderezhkin, Tatyana I. Rokitskaya, Elena A. Kotova, Yuri N. Antonenko
Summary: The linear 15-mer peptide gramicidin A (gA) forms a simple ion channel in lipid membranes. Two tightly connected gA subunits can exhibit synchronous opening, resulting in current transitions with higher amplitudes and longer lifetimes than single channels. The mechanism of this synchronous opening and closing is hypothesized to involve mixing of individual states and collective behavior of closely located channels. Similar phenomena may occur with other natural channel-forming peptides like alamethicin and syringomycin.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Morihiro Shimizu, Xinya Mi, Futoshi Toyoda, Akiko Kojima, Wei-Guang Ding, Yutaka Fukushima, Mariko Omatsu-Kanbe, Hirotoshi Kitagawa, Hiroshi Matsuura
Summary: Propofol acts as an allosteric modulator of cAMP-dependent gating in HCN channels, affecting the amplitude and voltage dependence of the channel opening.
Article
Chemistry, Medicinal
Xinghang Yuan, Di Zhang, Shengjun Mao, Qiantao Wang
Summary: This study utilized computational techniques to investigate the ion-conducting mechanism of GABA(A)R, the potential binding mechanism of propofol, and a new motion mechanism of TMD helices. The research aims to provide insights for future studies on ion-channel receptors, general anesthetics, and drug development.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Medicinal
Shijie Liu, Peipei Guo, Kun Wang, Shaoying Zhang, Ya Li, Juwen Shen, Lianghe Mei, Yangliang Ye, Qiansen Zhang, Huaiyu Yang
Summary: A ligand-to-ion activation mechanism was discovered for channels that bypasses their gates and is conserved across subfamilies with different gates.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Joseph W. Nors, Shipra Gupta, Marcel P. Goldschen-Ohm
Summary: The study investigates the role of the α(1)M2-M3 linker in the modulation of BZDs on pore opening, identifying the α(1)V279A mutation that significantly increases the energetic contribution of BZDs to pore opening. Other linker mutations have little effect on BZD efficiency but generally impair unliganded pore opening.
Article
Multidisciplinary Sciences
Ahmed Rohaim, Bram J. A. Vermeulen, Jing Li, Felix Kummerer, Federico Napoli, Lydia Blachowicz, Joao Medeiros-Silva, Benoit Roux, Markus Weingarth
Summary: C-type inactivation is physiologically important in Kv channels, but its structural basis is not fully understood. Previous knowledge about C-type inactivation is mainly derived from the bacterial KcsA channel, which has a different molecular environment compared to Kv channels. This study investigates a KcsA mutant that resembles Kv channels and reveals a distinct mechanism for C-type inactivation.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Yihan Wan, Dimitrios G. Anastasakis, Joseph Rodriguez, Murali Palangat, Prabhakar Gudla, George Zaki, Mayank Tandon, Gianluca Pegoraro, Carson C. Chow, Markus Hafner, Daniel R. Larson
Summary: This study establishes a platform for observing the dynamics of RNA synthesis and processing at a single molecule level, revealing transcriptional bursting in all genes and significant kinetic variation in splicing within introns. The research also uncovers widespread stochastic recursive splicing within introns and proposes a unified theoretical model to explain these phenomena.
Review
Biotechnology & Applied Microbiology
Koichi Yuki
Summary: This review highlights the importance of perioperative care for cancer surgery, particularly the role of general anesthesia in tumor resection, and the potential impact of anesthetics on cancer recurrence.
BIOMED RESEARCH INTERNATIONAL
(2021)
Article
Physiology
Guanxing Chen, Qin Li, Timothy I. Webb, Mark A. Hollywood, Jiusheng Yan
Summary: This study identifies positively charged peptides as modulators of BK channels, and reveals a role for the Ca2+-bowl site and the C-terminal positively charged regions of auxiliary gamma subunits in BK channel modulation. The positively charged peptides and the cationic HIV-1 Tat peptide can shift the voltage-gating of BK channels towards hyperpolarization. The modulatory effects of the synthetic peptides are reduced in the presence of Ca2+ and can be abolished by charge neutralization of the Ca2+-bowl site and high ionic strength.
JOURNAL OF GENERAL PHYSIOLOGY
(2023)
Editorial Material
Cell Biology
Ursula Storch, Michael Mederos y Schnitzler, Thomas Gudermann
Summary: The TRPC5 channel, a non-selective calcium-permeable cation channel, has emerged as a promising target for treating mental disorders and kidney diseases. Recent research has revealed the structural properties of TRPC5 channels, identified new drug binding sites, and highlighted the key role of the second messenger DAG in TRPC5 channel activation.
Article
Biophysics
Rohit Joshi, Pavel Pohl, Dita Strachotova, Petr Herman, Tomas Obsil, Veronika Obsilova
Summary: Nedd4-2, a ubiquitin ligase, is involved in the endocytosis and degradation of target molecules through interactions with 14-3-3 proteins. The binding of 14-3-3 induces structural rearrangement of Nedd4-2, affecting the mobility and emission properties of certain domains. In contrast, the active site of the HECT domain becomes more mobile upon 14-3-3 binding.
BIOPHYSICAL JOURNAL
(2022)
Review
Anesthesiology
T. E. F. Abbott, A. J. Fowler, P. Pelosi, M. Gama de Abreu, A. M. Moller, J. Canet, B. Creagh-Brown, M. Mythen, T. Gin, M. M. Lalu, E. Futier, M. P. Grocott, M. J. Schultz, R. M. Pearse
BRITISH JOURNAL OF ANAESTHESIA
(2018)
Review
Anesthesiology
D. J. Buggy, J. Freeman, M. Z. Johnson, K. Leslie, B. Riedel, D. I. Sessler, A. Kurz, V. Gottumukkala, T. Short, N. Pace, P. M. Myles
BRITISH JOURNAL OF ANAESTHESIA
(2018)
Review
Anesthesiology
L. Evered, B. Silbert, D. S. Knopman, D. A. Scott, S. T. DeKosky, L. S. Rasmussen, E. S. Oh, G. Crosby, M. Berger, R. G. Eckenhoff
BRITISH JOURNAL OF ANAESTHESIA
(2018)
Article
Biochemistry & Molecular Biology
Kellie A. Woll, Xiaojuan Zhou, Natarajan V. Bhanu, Benjamin A. Garcia, Manuel Covarrubias, Keith W. Miller, Roderic G. Eckenhoff
Article
Biochemistry & Molecular Biology
Lan Cheng, Moza Al-Owais, Manuel L. Covarrubias, Walter J. Koch, David. R. Manning, Chris Peers, Natalia A. Riobo-Del Galdo
JOURNAL OF BIOLOGICAL CHEMISTRY
(2018)
Article
Physiology
Elaine Yang, Daniele Granata, Roderic G. Eckenhoff, Vincenzo Carnevale, Manuel Covarrubias
JOURNAL OF GENERAL PHYSIOLOGY
(2018)
Article
Physiology
Yali Wang, Elaine Yang, Marta M. Wells, Vasyl Bondarenko, Kellie Woll, Vincenzo Carnevale, Daniele Granata, Michael L. Klein, Roderic G. Eckenhoff, William P. Dailey, Manuel Covarrubias, Pei Tang, Yan Xu
JOURNAL OF GENERAL PHYSIOLOGY
(2018)
Article
Neurosciences
Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C. Lepore, Manuel Covarrubias
JOURNAL OF NEUROSCIENCE
(2018)
Review
Neurosciences
Benjamin M. Zemel, David M. Ritter, Manuel Covarrubias, Tanziyah Muqeem
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2018)
Article
Biochemistry & Molecular Biology
Benjamin M. Zemel, Lianteng Zhi, Eric V. Brown, Stephen R. Tymanskyj, Qiansheng Liang, Manuel Covarrubias
Summary: The study suggests that a physical interaction between Kv3.4 channel and functional PKC epsilon primarily determines its stability and localization in DRG neurons, without significantly affecting its gating.
Article
Biochemistry & Molecular Biology
Kristine S. Ojala, Scott P. Ginebaugh, Man Wu, Evan W. Miller, Gloria Ortiz, Manuel Covarrubias, Stephen D. Meriney
Summary: Research shows that the main mechanism of action of 3,4-DAP at the neuromuscular junction is through acting on Kv channels to mediate AP broadening and enhance transmitter release.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Neurosciences
Tyler D. Alexander, Tanziyah Muqeem, Lianteng Zhi, Stephen R. Tymanskyj, Manuel Covarrubias
Summary: The Kv3.4 channel plays a role in regulating action potential in nociceptors and synaptic transmission in the spinal cord, and this regulation is influenced by the phosphorylation status of the Kv3.4 channel. Experimental results on rat dorsal root ganglion neurons suggest that the phosphorylation status of Kv3.4 affects current and action potential duration.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Medicine, Research & Experimental
Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Summary: GUCY2C signaling in neuropod cells plays a crucial role in visceral pain, and FDA-approved GUCY2C agonists can alleviate visceral pain in patients with chronic constipation syndromes. Studies on neural currents and action potentials indicate that neuropod cells, enriched with GUCY2C receptors, have significant regulatory effects.
JOURNAL OF CLINICAL INVESTIGATION
(2023)