Article
Multidisciplinary Sciences
Tamer M. Gamal El-Din, Timothy Lantin, Christopher W. Tschumi, Barbara Juarez, Meagan Quinlan, Julia H. Hayano, Jin Li, Larry S. Zweifel, William A. Catterall
Summary: Autism spectrum disorder affects over 1% of children in the United States, resulting in social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis through genome sequencing has identified over 500 genes with mutations in ASD, suggesting that altered control of action potential generation by gating pore current through mutant K(v)7 channels may be a potential pathogenic mechanism in autism.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
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
Pharmacology & Pharmacy
Frank S. Choveau, Ismail Ben Soussia, Delphine Bichet, Chatelain C. Franck, Sylvain Feliciangeli, Florian Lesage
Summary: This study investigates how the inhibitory potassium channels of the TREK1/TRAAK family are affected by multiple stimuli like temperature, membrane stretch, polyunsaturated fatty acids, and pH. Through pharmacological experiments, it was found that the cytoplasmic domain pCt, arachidonic acid, and extracellular pH converge to the same gate within the channel. Additionally, the study provides evidence that the up and down conformations identified by crystallography do not correspond to the open and closed states of these channels.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Cell Biology
Weiyuan Huang, Yue Ke, Jianping Zhu, Shuai Liu, Jin Cong, Hailin Ye, Yanwu Guo, Kewan Wang, Zhenhai Zhang, Wenxiang Meng, Tian-Ming Gao, Heiko J. Luhmann, Werner Kilb, Rongqing Chen
Summary: Depolarization-induced shunting inhibition (DShI) mediates non-synaptic, neuronal intrinsic short-term plasticity, which suppresses action potential generation and postsynaptic responses. The TRESK channel significantly contributes to DShI and may represent a therapeutic target for antiepileptic drugs.
Article
Multidisciplinary Sciences
Toby S. Turney, Vivian Li, Stephen G. Brohawn
Summary: Researchers use cryo-EM and electrophysiology to discover the gating mechanism of the TWIK1 channel in response to lowered pH. They find that conformational changes at the selectivity filter lead to the closure of the channel. This study provides mechanistic insights into the pH-gating of TWIK1 and sheds light on the diversity of gating mechanisms in K+ channels.
NATURE COMMUNICATIONS
(2022)
Article
Gastroenterology & Hepatology
Steffen Pfeuffer, Thomas Muentefering, Leoni Rolfes, Frederike Anne Straeten, Susann Eichler, Joel Gruchot, Vera Dobelmann, Tim Prozorovski, Boris Goerg, Mihael Vucur, Carsten Berndt, Patrick Kury, Tobias Ruck, Stefan Bittner, Dominik Bettenworth, Thomas Budde, Tom Luedde, Sven G. Meuth
Summary: KCNK9 regulates inflammatory bowel disease by modulating intracellular calcium concentration and supporting epithelial cell survival. Its deficiency or pharmacologic blockade worsens colitis, while increased expression of KCNK3 is associated with beneficial outcomes but does not prevent apoptosis.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2022)
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
David K. Jones
Summary: Cardiac hERG channels consist of hERG 1a and hERG 1b subunits, which drive cardiac action potential repolarization by regulating the movement of voltage sensor domains (VSDs). This study found that VSD relaxation delays pore closure during repolarization and that the hERG 1a PAS domain plays a role in regulating VSD movement. These findings provide the first recordings of hERG gating charge at physiological temperature and demonstrate the presence of VSD relaxation in hERG channels at physiological temperature.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Grigory Maksaev, Michael Bruendl-Jirout, Anna Stary-Weinzinger, Eva-Maria Zangerl-Plessl, Sun-Joo Lee, Colin G. Nichols
Summary: The authors introduced negative charges in Kir2.2 channels, resulting in pH-dependent sub-conductances. Molecular dynamics simulations show that protonation leads to step-wise alterations of ion pooling and conductance, appearing as gated substates. Single-channel recordings reveal pH-dependent subconductance behaviors.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Jintao Wang, Huan Liu, Zhuolin Sun, Xinyi Zou, Zixuan Zhang, Xiaofeng Wei, Lanying Pan, Antony Stalin, Wei Zhao, Yuan Chen
Summary: In this study, the TWIK1 current was increased by using a high concentration of ammonium solution. The inhibitory effect of magnolol on TWIK1 was observed, and it was found that G229 and T225 on the P2-pore helix play an important role in TWIK1 inhibition.
Article
Biochemistry & Molecular Biology
Piao Zhao, Cheng Tang, Yuqin Yang, Zhen Xiao, Samantha Perez-Miller, Heng Zhang, Guoqing Luo, Hao Liu, Yaqi Li, Qingyi Liao, Fan Yang, Hao Dong, Rajesh Khanna, Zhonghua Liu
Summary: This study reveals the proton gating and protonation-independent voltage gating mechanisms of the PAC channel, using its unique bifunctional modulator C77304, with implications for drug development.
Review
Cell Biology
Felix Wiedmann, Norbert Frey, Constanze Schmidt
Summary: K-2P channels play important roles in maintaining resting membrane potential, modulating action potential repolarization, and regulating physiological processes. Dysregulation of K-2P channels in cardiovascular diseases may have therapeutic significance. Channels like K(2P)3.1 (TASK-1) and K(2P)2.1 (TREK-1) are associated with atrial fibrillation and cardiac remodeling, respectively.
Article
Multidisciplinary Sciences
Yoshiaki Kise, Go Kasuya, Hiroyuki H. Okamoto, Daichi Yamanouchi, Kan Kobayashi, Tsukasa Kusakizako, Tomohiro Nishizawa, Koichi Nakajo, Osamu Nureki
Summary: Mechanisms of modulation of Kv4 channel complexes by auxiliary subunits are central to the physiological function of channels in the brain and heart. The structures of Kv4.2-KChIP1 and Kv4.2-DPP6S complexes reveal that KChIP1 prevents N-type inactivation and stabilizes the S6 conformation, while DPP6S interacts with the S1 and S2 helices to accelerate voltage-dependent movement. KChIP1 and DPP6S do not directly interact with each other in the ternary complex, suggesting two distinct modes of modulation contribute to evoke A-type currents.
Article
Biochemical Research Methods
Monika Richter-Laskowska, Paulina Trybek, Piotr Bednarczyk, Agata Wawrzkiewicz-Jalowiecka
Summary: Research demonstrates that flavanones, including naringenin, show promise as regulators of the large conductance voltage- and Ca2+- activated K+ channels on the inner mitochondrial membrane, mitoBK. The molecular mechanism of mitoBK-Nar interactions and their effects on conformational dynamics remain unclear. Artificial intelligence methods, such as k-NN and shapelet learning, were used to analyze dwell-time series of mitoBK channels at different voltages and Nar concentrations, revealing stimulus-specific patterns of channel gating and the complex interactions between the channel gate, voltage sensor, and Nar-binding site. In addition, long-range intra-sensor interactions between VSD and the Nar-coordination site were found to play a role in Nar-activation at deeply depolarized membranes.
PLOS COMPUTATIONAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Loretta Ferrera, Raffaella Barbieri, Cristiana Picco, Paolo Zuccolini, Alessia Remigante, Sara Bertelli, Maria Rita Fumagalli, Giovanni Zifarelli, Caterina A. M. La Porta, Paola Gavazzo, Michael Pusch
Summary: The response to oxidative stimulation in melanoma cells involves the activation of potassium currents and an increase in intracellular calcium levels, mediated by BK, KCa3.1, and TRPM2 channels. Differences in the expression levels of these channels in different cell lines may play a crucial role in melanoma progression. Targeting these ion channels pharmacologically could be a novel strategy to reduce the metastatic potential of melanoma cells alongside traditional treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Alistair Mathie, Emma L. Veale, Kevin P. Cunningham, Robyn G. Holden, Paul D. Wright
Summary: K2P channels play a crucial role in regulating cell activity and pharmacological modulation of these channels could be beneficial for various conditions. Recent studies on K2P channel structures and small-molecule compounds provide insights for the development of selective activators and inhibitors targeting these channels.
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 61, 2021
(2021)
Article
Pharmacology & Pharmacy
Stephen P. H. Alexander, Doriano Fabbro, Eamonn Kelly, Alistair Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Adam J. Pawson, Christopher Southan, Jamie A. Davies, Detlev Boison, Kathryn Elisa Burns, Carmen Dessauer, Jurg Gertsch, Nuala Ann Helsby, Angelo A. Izzo, Doris Koesling, Rennolds Ostrom, Nigel J. Pyne, Susan Pyne, Michael Russwurm, Roland Seifert, Johannes-Peter Stasch, Mario van der Stelt, Albert van der Vliet, Val Watts, Szu Shen Wong
Summary: The Concise Guide to PHARMACOLOGY 2021/22 provides concise overviews of nearly 1900 human drug targets, with an emphasis on selective pharmacology, linking to an open access knowledgebase for more detailed information. Produced in collaboration with NC-IUPHAR, it offers official IUPHAR classification and nomenclature for human drug targets.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Stephen P. H. Alexander, Doriano Fabbro, Eamonn Kelly, Alistair Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Adam J. Pawson, Christopher Southan, Jamie A. Davies, Annie Beuve, Peter Brouckaert, Clare Bryant, John C. Burnett, Richard W. Farndale, Andreas Friebe, John Garthwaite, AdrianJ Hobbs, Gavin E. Jarvis, Michaela Kuhn, David MacEwan, Tom P. Monie, Andreas Papapetropoulos, Lincoln R. Potter, Harald H. H. W. Schmidt, Csaba Szabo, Scott A. Waldman
Summary: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth edition in a biennial series, offering concise overviews of nearly 1900 human drug targets with an emphasis on selective pharmacology. It is designed for easy comparison of related targets and provides nomenclature guidance, summary information on pharmacological tools, and suggestions for further reading. The guide is produced in collaboration with the NC-IUPHAR to provide official classification and nomenclature for human drug targets.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Stephen P. H. Alexander, Arthur Christopoulos, Anthony P. Davenport, Eamonn Kelly, Alistair Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Adam J. Pawson, Christopher Southan, Jamie A. Davies, Maria Pia Abbracchio, Wayne Alexander, Khaled Al-hosaini, Magnus Baeck, Nicholas M. Barnes, Ross Bathgate, Jean-Martin Beaulieu, Kenneth E. Bernstein, Bernhard Bettler, Nigel J. M. Birdsall, Victoria Blaho, Francois Boulay, Corinne Bousquet, Hans Braeuner-Osborne, Geoffrey Burnstock, Girolamo Calo, Justo P. Castano, KevinJ Catt, Stefania Ceruti, Paul Chazot, Nan Chiang, Bice Chini, Jerold Chun, Antonia Cianciulli, Olivier Civelli, Lucie H. Clapp, Rejean Couture, Zsolt Csaba, Claes Dahlgren, Gordon Dent, Khuraijam Dhanachandra Singh, Steven D. Douglas, Pascal Dournaud, Satoru Eguchi, Emanuel Escher, Edward J. Filardo, Tung Fong, Marta Fumagalli, Raul R. Gainetdinov, Marc de Gasparo, Craig Gerard, Marvin Gershengorn, Fernand Gobeil, Theodore L. Goodfriend, Cyril Goudet, Karen J. Gregory, Andrew L. Gundlach, Joerg Hamann, Julien Hanson, Richard L. Hauger, Debbie L. Hay, Akos Heinemann, Morley D. Hollenberg, Nicholas D. Holliday, Mastgugu Horiuchi, Daniel Hoyer, Laszlo Hunyady, Ahsan Husain, Adriaan P. IJzerman, Tadashi Inagami, Kenneth A. Jacobson, Robert T. Jensen, Ralf Jockers, Deepa Jonnalagadda, Sadashiva Karnik, Klemens Kaupmann, Jacqueline Kemp, Charles Kennedy, Yasuyuki Kihara, Takio Kitazawa, Pawel Kozielewicz, Hans-Juergen Kreienkamp, Jyrki P. Kukkonen, Tobias Langenhan, Katie Leach, Davide Lecca, John D. Lee, Susan E. Leeman, Jerome Leprince, Xaria X. Li, Tom Lloyd Williams, Stephen J. Lolait, Amelie Lupp, Robyn Macrae, Janet Maguire, Jean Mazella, Craig A. McArdle, Shlomo Melmed, Martin C. Michel, Laurence J. Miller, Vincenzo Mitolo, Bernard Mouillac, Christa E. Mueller, Philip Murphy, Jean-Louis Nahon, Tony Ngo, Xavier Norel, Duuamene Nyimanu, Anne-Marie Ocarroll, Stefan Offermanns, Maria Antonietta Panaro, Marc Parmentier, Roger G. Pertwee, Jean-Philippe Pin, Eric R. Prossnitz, Mark Quinn, Rithwik Ramachandran, Manisha Ray, Rainer K. Reinscheid, Philippe Rondard, G. Enrico Rovati, Chiara Ruzza, Gareth J. Sanger, Torsten Schoeneberg, Gunnar Schulte, Stefan Schulz, Deborah L. Segaloff, Charles N. Serhan, Leigh A. Stoddart, Yukihiko Sugimoto, Roger Summers, Valerie P. Tan, David Thal, Walter (Wally) Thomas, PieterB M. W. M. Timmermans, Kalyan Tirupula, Giovanni Tulipano, Hamiyet Unal, Thomas Unger, Celine Valant, Patrick Vanderheyden, David Vaudry, Hubert Vaudry, Jean-Pierre Vilardaga, Christopher S. Walker, Ji Ming Wang, Donald T. Ward, Hans-Juergen Wester, Gary B. Willars, Trent M. Woodruff, Chengcan Yao, Richard D. Ye
Summary: The Concise Guide to PHARMACOLOGY 2021/22 presents concise overviews of nearly 1900 human drug targets with an emphasis on selective pharmacology, along with links to a more detailed knowledgebase. It serves as a permanent, citable record for researchers, providing useful information in the field of pharmacology.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Stephen P. H. Alexander, John A. Cidlowski, Eamonn Kelly, Alistair Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Adam J. Pawson, Christopher Southan, Jamie A. Davies, Laurel Coons, Peter J. Fuller, Kenneth S. Korach, Morag J. Young
Summary: The Concise Guide to PHARMACOLOGY 2021/22 offers concise overviews of nearly 1900 human drug targets, predominantly in tabular format, emphasizing on selective pharmacology. The guide provides a simplified, citable record compared to the website information, and is designed for comparison of related targets from mid-2021.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Stephen P. H. Alexander, Eamonn Kelly, Alistair Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Adam J. Pawson, Christopher Southan, Jamie A. Davies, Laura Amarosi, Catriona M. H. Anderson, Philip Mark Beart, Stefan Broer, Paul A. Dawson, Bruno Hagenbuch, James R. Hammond, Ken-ichi Inui, Yoshikatsu Kanai, Stephan Kemp, Gavin Stewart, David T. Thwaites, Tiziano Verri
Summary: The Concise Guide to PHARMACOLOGY 2021/22 is a comprehensive publication providing concise overviews of nearly 1900 human drug targets with an emphasis on selective pharmacology. It covers six major pharmacological targets, offering information on the best available pharmacological tools and suggestions for further reading. The guide is a valuable resource for researchers and professionals in the field of pharmacology.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Kevin P. Cunningham, Lucie H. Clapp, Alistair Mathie, Emma L. Veale
Summary: Pulmonary arterial hypertension (PAH) is a severe vascular remodeling disease with high morbidity and mortality rates. Treprostinil is an FDA and WHO approved treatment for PAH, but its limitation includes potential severe pain in some patients which may affect compliance.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
D. McCoull, E. L. Veale, Y. Walsh, L. Byrom, T. Avkiran, J. M. Large, E. Vaitone, F. Gaffey, J. Jerman, A. Mathie, P. D. Wright
Summary: TRAAK, a mechanosensitive potassium channel, is a potential target for novel analgesics. Aprepitant was identified through high throughput screening as a small molecule activator of TRAAK, demonstrating selectivity and no activation of other K2P channels.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Margot A. Cousin, Emma L. Veale, Nikita R. Dsouza, Swarnendu Tripathi, Robyn G. Holden, Maria Arelin, Geoffrey Beek, Mir Reza Bekheirnia, Jasmin Beygo, Vikas Bhambhani, Martin Bialer, Stefania Bigoni, Cyrus Boelman, Jenny Carmichael, Thomas Courtin, Benjamin Cogne, Ivana Dabaj, Diane Doummar, Laura Fazilleau, Alessandra Ferlini, Ralitza H. Gavrilova, John M. Graham, Tobias B. Haack, Jane Juusola, Sarina G. Kant, Saima Kayani, Boris Keren, Petra Ketteler, Chiara Kloeckner, Tamara T. Koopmann, Teresa M. Kruisselbrink, Alma Kuechler, Laetitia Lambert, Xenia Latypova, Robert Roger Lebel, Magalie S. Leduc, Emanuela Leonardi, Andrea M. Lewis, Wendy Liew, Keren Machol, Samir Mardini, Kirsty McWalter, Cyril Mignot, Julie McLaughlin, Alessandra Murgia, Vinodh Narayanan, Caroline Nava, Sonja Neuser, Mathilde Nizon, Davide Ognibene, Joohyun Park, Konrad Platzer, Celine Poirsier, Maximilian Radtke, Keri Ramsey, Cassandra K. Runke, Maria J. Guillen Sacoto, Fernando Scaglia, Marwan Shinawi, Stephanie Spranger, Ee Shien Tan, John Taylor, Anne-Sophie Trentesaux, Filippo Vairo, Rebecca Willaert, Neda Zadeh, Raul Urrutia, Dusica Babovic-Vuksanovic, Michael T. Zimmermann, Alistair Mathie, Eric W. Klee
Summary: This study describes the mechanisms underlying KCNK9 imprinting syndrome (KIS) by identifying 15 novel KCNK9 alterations from 47 KIS-affected individuals. The study reveals the broader genetic and phenotypic variability for KIS and demonstrates the impact of KCNK9 variants on TASK3 channel function and regulation.
Article
Cell Biology
Sandra Medrano-Garcia, Daniel Morales-Cano, Bianca Barreira, Alba Vera-Zambrano, Rahul Kumar, Djuro Kosanovic, Ralph Theo Schermuly, Brian B. Graham, Francisco Perez-Vizcaino, Alistair Mathie, Rajkumar Savai, Soni Pullamseti, Ghazwan Butrous, Edgar Fernandez-Malave, Angel Cogolludo
Summary: HIV and Schistosoma co-infection has a significant impact on pulmonary vascular disease, as shown in this study using an animal model. Co-infected mice exhibited increased pulmonary arterial pressure, impaired endothelial function, vessel obstructions, and perivascular fibrosis. Additionally, the immune response was compromised and cytokine expression was altered, leading to aggravated pulmonary vascular pathology.
Article
Pharmacology & Pharmacy
Emma L. Veale, Alessia Golluscio, Katheryn Grand, John M. Graham Jr, Alistair Mathie
Summary: This study describes a novel variant in the KCNB1 gene associated with global developmental delays, mild hypotonia, and joint laxity but without seizures. The variant leads to a gain-of-function of the K(V)2.1 channel with altered steady-state inactivation and reduced sensitivity to guanxitoxin-1E.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yvonne Walsh, Michael Leach, Emma L. Veale, Alistair Mathie
Summary: In this study, the inhibitory effects of the anticonvulsant lamotrigine, sipatrigine, and CEN-092 on TREK and TRESK K2P channels were investigated. Sipatrigine was found to be a more potent inhibitor compared to lamotrigine, with slight differences in potency between TREK-1 and TRESK channels. Mutation of certain residues affected the inhibition by sipatrigine and lamotrigine, indicating different mechanisms of action for these compounds.
BIOCHEMISTRY AND BIOPHYSICS REPORTS
(2021)