Article
Chemistry, Medicinal
Mizael C. Araujo, Suzany H. S. Soczek, Jaqueline P. Pontes, Bruno A. S. Pinto, Lucas M. Franca, Bruna da Silva Soley, Gabriela S. Santos, Warlison F. de Silva Saminez, Fernanda K. M. Fernandes, Joao L. do Carmo Lima, Daniele Maria-Ferreira, Joao F. S. Rodrigues, Nara L. M. Quintao, Valerio Monteiro-Neto, Antonio M. A. Paes, Elizabeth S. Fernandes
Summary: Excessive consumption of sugar causes metabolic imbalances and is associated with increased obesity rates worldwide. This study investigated the effects of a TRPC4/TRPC5 blocker, ML204, on the metabolic imbalances caused by early exposure to a sucrose-enriched diet in mice. The results suggest that TRPC4/TRPC5 have a protective effect against the metabolic imbalances induced by sucrose ingestion.
Article
Multidisciplinary Sciences
Laura Bernal, Pamela Sotelo-Hitschfeld, Christine Koenig, Viktor Sinica, Amanda Wyatt, Zoltan Winter, Alexander Hein, Filip Touska, Susanne Reinhardt, Aaron Tragl, Ricardo Kusuda, Philipp Wartenberg, Allen Sclaroff, John D. Pfeifer, Fabien Ectors, Andreas Dahl, Marc Freichel, Viktorie Vlachova, Sebastian Brauchi, Carolina Roza, Ulrich Boehm, David E. Clapham, Jochen K. Lennerz, Katharina Zimmermann
Summary: This study clarifies the molecular and cellular components of the dental cold sensing system, highlighting the role of TRPC5 and TRPA1 in cold sensing in teeth. Odontoblasts are shown to be the direct site of cold transduction. This expands our understanding of the mechanisms behind cold sensitivity in teeth.
Article
Genetics & Heredity
Wenjun Zeng, Yinan Ji, Haiping Zhang, Liusheng Chen, Li Du, Ruiwei Guo
Summary: The study explored target molecules to inhibit VSMCs proliferation without affecting VECs, finding that simultaneous inhibition of TRPC4 and TRPC5 can effectively achieve this goal, providing novel targets for developing pharmacological agents for drug-eluting stents.
Article
Chemistry, Multidisciplinary
Markus Mueller, Konstantin Niemeyer, Nicole Urban, Navin K. Ojha, Frank Zufall, Trese Leinders-Zufall, Michael Schaefer, Oliver Thorn-Seshold
Summary: In this study, the first photoswitchable TRPC5-modulator, BTDAzo, was developed and shown to effectively control TRPC5 activity in cell culture and mouse brain slices. BTDAzo is the first reported azo-benzothiadiazine and exhibits strong two-colour photoswitching. Its ability to control TRPC5 in various channel biology settings makes it suitable for dynamically reversible photoswitching studies in TRP channel biology, aiming to decipher the biological roles of this important ion channel.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Medicine, Research & Experimental
Dariia O. Dryn, Mariia I. Melnyk, Robin S. Bon, David J. Beech, Alexander V. Zholos
Summary: This study investigated the effects of the TRPC4 inhibitor Pico145 on mICAT and Ca2+ signaling in mouse ileal myocytes, as well as on intestinal motility. The results showed that Pico145 effectively inhibited mICAT current and carbachol-induced intracellular Ca2+ rises, while having a weaker effect on the current activated by a TRPC4 agonist. Functional assays demonstrated that Pico145 concentration-dependently suppressed smooth muscle contractions and delayed postprandial intestinal transit.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Cell Biology
Alexandra Ptakova, Michal Mitro, Lucie Zimova, Viktorie Vlachova
Summary: TRPC5 is a cold-sensitive channel protein, and its sensitivity is determined by the phosphorylation status of the protein and intracellular calcium homeostasis.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Multidisciplinary Sciences
Jongdae Won, Jinsung Kim, Hyeongseop Jeong, Jinhyeong Kim, Shasha Feng, Byeongseok Jeong, Misun Kwak, Juyeon Ko, Wonpil Im, Insuk So, Hyung Ho Lee
Summary: The article reveals the direct interaction between G-protein coupled receptors (GPCRs) and ion channels using cryo-electron microscopy structures, shedding light on the structural framework of the cross-talk between the two major classes of transmembrane proteins. The study demonstrates that G alpha increases the sensitivity of TRPC5 to PIP2, making it more easily opened in the cell membrane, which is physiologically regulated.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Lingli He, Zhuoya Yu, Ze Geng, Zhuo Huang, Changjiang Zhang, Yanli Dong, Yiwei Gao, Yuhang Wang, Qihao Chen, Le Sun, Xinyue Ma, Bo Huang, Xiaoqun Wang, Yan Zhao
Summary: This study determines the structures of the human T-type Ca(v)3.3 channel and investigates the effects of antihypertensive, antispasmodic, and antipsychotic drugs. The structures provide insights into the channel gating, drug recognition, and actions, which can guide the development of subtype-specific drugs for related disorders.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Kirin D. Gada, Mengmeng Chang, Aishwarya Chandrashekar, Leigh D. Plant, Sami F. Noujaim, Diomedes E. Logothetis
Summary: G-protein-gated inwardly rectifying potassium (GIRK) channel activity is regulated by phosphatidylinositol-4,5-bisphosphate (PI 4,5P(2)), and PKC epsilon plays a role in the activation of GIRK channels in cardiac atrial cells and human stem cell-derived atrial cardiomyocytes. PKC epsilon enhances the interaction between GIRK4 and GIRK1/4 with PIP2, leading to increased channel activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Neurosciences
Cody A. Boyle, Binqi Hu, Kati L. Quaintance, Saobo Lei
Summary: The activation of V-1a vasopressin receptors in the medial nucleus of central amygdala facilitates neuronal excitability primarily by opening TRPC5 channels. Additionally, AVP excitatory effects involve suppressing Kir channels and PLC beta-mediated depletion of PIP2. Intracellular Ca2+ release and PKC activity are not required for V-1a receptor-mediated excitation in CeM neurons.
JOURNAL OF PHYSIOLOGY-LONDON
(2021)
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
Multidisciplinary Sciences
Jin-Bin Tian, Jane Yang, William C. Joslin, Veit Flockerzi, Steven A. Prescott, Lutz Birnbaumer, Michael X. Zhu
Summary: Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel that can sense neurotransmission through G(q/11)- and G(i/o)-coupled receptors. TRPC4 mediates a depolarizing plateau in lateral septal neurons, shutting down action potential firing, and the duration of the depolarization depends on the strength of G(i/o) stimulation. The depolarizing plateau is dependent on G(q/11)-coupled group I metabotropic glutamate receptors and G(i/o)-coupled gamma-aminobutyric acid type B receptors, while the hyperpolarization is mediated by G(i/o) activation of GIRK channels.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Zhenghao Chen, Youquan Zhao, Ye Tian, Rui Cao, Donghao Shang
Summary: In this study, the expression level and prognostic value of TRP family genes in pan-cancer tissues were comprehensively analyzed. The results showed differential expression of TRP family genes in tumor and para-carcinoma tissues, and significant correlations with prognosis. Additionally, TRP family gene expression was associated with tumor microenvironment, stemness score, immune subtype, drug sensitivity, and immunotherapy outcome. These findings suggest that TRP family genes may play an important role in cancer progression and could be potential pan-cancer targets.
Article
Chemistry, Multidisciplinary
Lina T. Al Kury, Dimitrios Papandreou, Vasyl V. Hurmach, Dariia O. Dryn, Mariia I. Melnyk, Maxim O. Platonov, Yuriy I. Prylutskyy, Uwe Ritter, Peter Scharff, Alexander V. Zholos
Summary: This study demonstrates that carboxylated single-walled carbon nanotubes can inhibit muscarinic receptor cation current in mouse ileal smooth muscle cells, mainly through direct blocking of the TRPC4 channel.
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
Pharmacology & Pharmacy
Katharina Held, Vincenzo Davide Aloi, Ana Cristina Nogueira Freitas, Annelies Janssens, Andrei Segal, Julia Przibilla, Stephan Ernst Philipp, Yu Tian Wang, Thomas Voets, Joris Vriens
Summary: This study compares the pharmacological properties of different splice variants of TRPM3, demonstrating that the length of the pore-forming loop in the alternative splicing region defines the channel's activation by specific compounds.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Cell Biology
Anouar Belkacemi, Andreas Beck, Barbara Wardas, Petra Weissgerber, Veit Flockerzi
Summary: The Cav beta 3 subunit desensitizes cells to low concentrations of IP3, resulting in altered Ca2+ signaling and cellular functions. This property is specific to Cav beta 3 and is not shared by other Cav beta subunits.
Article
Respiratory System
Tian Jiang, Rudi Samapati, Sergej Klassen, Disi Lei, Lasti Erfinanda, Vera Jankowski, Szandor Simmons, Jun Yin, Christoph Arenz, Alexander Dietrich, Thomas Gudermann, Dieter Adam, Michael Schaefer, Joachim Jankowski, Veit Flockerzi, Rolf Nuesing, Stefan Uhlig, Wolfgang M. Kuebler
Summary: The study found that EP3 receptor activation triggers pulmonary edema through Gi-dependent activation of PLC and subsequent SrcFK-dependent tyrosine phosphorylation of TRPC6. In PAF-induced lung edema, this TRPC6 activation coincides with ASMase-dependent caveolar recruitment of TRPC6, resulting in rapid endothelial Ca2+ influx and barrier failure.
EUROPEAN RESPIRATORY JOURNAL
(2022)
Article
Chemistry, Physical
Nicolas Kuenzel, Volkhard Helms
Summary: PDZ domains form a large family of adaptor proteins that bind to the C-terminal tails of their binding partner proteins. This study used molecular dynamics simulations and alchemical free energy calculations to investigate the binding of different peptide sequences to PDZ domains. The simulations accurately reproduced the known binding characteristics and revealed the importance of specific amino acid residues in the binding process. However, there were some inaccuracies in predicting the binding of phosphorylated peptides, which differed from experimental results.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Multidisciplinary Sciences
Jin-Bin Tian, Jane Yang, William C. Joslin, Veit Flockerzi, Steven A. Prescott, Lutz Birnbaumer, Michael X. Zhu
Summary: Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel that can sense neurotransmission through G(q/11)- and G(i/o)-coupled receptors. TRPC4 mediates a depolarizing plateau in lateral septal neurons, shutting down action potential firing, and the duration of the depolarization depends on the strength of G(i/o) stimulation. The depolarizing plateau is dependent on G(q/11)-coupled group I metabotropic glutamate receptors and G(i/o)-coupled gamma-aminobutyric acid type B receptors, while the hyperpolarization is mediated by G(i/o) activation of GIRK channels.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Sarah O'Keefe, Pratiti Bhadra, Kwabena B. Duah, Guanghui Zong, Levise Tenay, Lauren Andrews, Hayden Schneider, Ashley Anderson, Zhijian Hu, Hazim S. Aljewari, Belinda S. Hall, Rachel E. Simmonds, Volkhard Helms, Stephen High, Wei Q. Shi
Summary: This study demonstrates that macrocyclic integrity is not necessary for the cytotoxic inhibition of Sec61-dependent protein translocation by Ipom-F. The researchers find that open-chain analogues can interact with multiple sites on the Sec61 alpha subunit. Additionally, they discover a stereochemically simplified analogue that is more potent and easier to synthesize.
Article
Cell Biology
Andrea Tirincsi, Sarah O'Keefe, Duy Nguyen, Mark Sicking, Johanna Dudek, Friedrich Forster, Martin Jung, Drazena Hadzibeganovic, Volkhard Helms, Stephen High, Richard Zimmermann, Sven Lang
Summary: Importing proteins into the endoplasmic reticulum is crucial for approximately 30% of the human proteome, involving precursor protein targeting and insertion or translocation across the ER membrane with the help of signals in precursor polypeptides. Little is known about the SRP-independent/SND pathway, and our study aimed to identify additional components and characterize the client spectrum of this pathway, finding that SND clients are predominantly membrane proteins.
Article
Chemistry, Medicinal
Andreas Denger, Volkhard Helms
Summary: This study focuses on the annotation of substrate molecules for membrane transporters and the use of machine learning classifiers. The research found that by selecting an appropriate protein sequence feature dataset, organism-specific robust classifiers can be trained, achieving high accuracy in predicting substrates for membrane transporters.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Cell Biology
Thomas Sell, Christian Klotz, Matthias M. Fischer, Rosario Astaburuaga-Garcia, Susanne Krug, Jarno Drost, Hans Clevers, Christine Sers, Markus Morkel, Nils Bluethgen
Summary: Colorectal cancer progression is closely related to deregulation of intestinal differentiation trajectory. The sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish cancer hallmarks. Mass cytometry of isogenic human colon and patient-derived cancer organoids reveals a differentiation axis from normal to cancer states, shaped by the driver mutations. Cells along this axis can be influenced by subsequent mutations to promote or restrict stem cell properties. Nodes of the cancer cell signaling network remain coupled to the differentiation state. Single-cell RNA sequencing links protein signaling network to transcriptomic states with biological and clinical importance.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Barbara Wardas, Jochen G. Schneider, Norbert Klugbauer, Veit Flockerzi, Andreas Beck
Summary: Englerin A (EA) is a potent agonist that blocks the functions of CaV1.2 and T-type CaV channels. This study is significant for understanding the mechanism of action of EA and its potential in breakthrough cancer treatment.
MOLECULAR PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Marcel S. Woo, Friederike Ufer, Jana K. Sonner, Anouar Belkacemi, Joseph Tintelnot, Pablo J. Saez, Paula F. Krieg, Christina Mayer, Lars Binkle-Ladisch, Jan Broder Engler, Simone Bauer, Nina Kursawe, Vanessa Vieira, Stefanie Mannebach, Marc Freichel, Veit Flockerzi, Pablo Vargas, Manuel A. Friese
Summary: The study identifies CACNB3 as a master regulator of ATP-dependent migDC migration, which plays a crucial role in regulating tissue-specific immune responses during injury and inflammation.
Article
Cell Biology
Megan R. Beggs, Kennedi Young, Allen Plain, Debbie D. O'Neill, Ahsan Raza, Veit Flockerzi, Henrik Dimke, R. Todd Alexander
Summary: We found that intestinal permeability to calcium is higher in suckling animals due to increased expression of claudin-2, a calcium channel protein, which is stimulated by epidermal growth factor (EGF) in breast milk. Loss of the claudin-2 pathway leads to decreased bone mineralization in 2-week-old mice.
Letter
Biochemistry & Molecular Biology
Caroline Diener, Martin Hart, Claudia Fecher-Trost, Jessica Knittel, Stefanie Rheinheimer, Markus R. Meyer, Jens Mayer, Veit Flockerzi, Andreas Keller, Eckart Meese
Summary: One widely accepted concept in biology is the potentiated cooperative effect of multiple miRNAs on the same target, despite insufficient experimental evidence. The quantity and quality of required side constraints of cooperative binding remain largely unknown. In this study, we selected 15 joint target genes, representing various 3'UTR binding site constellations, and found different cooperative scenarios between miR-21-5p and miR-155-5p. Surprisingly, our experiments provided stronger evidence for cooperative miRNA effects than originally postulated, highlighting the need to refine the definition of targetomes specified for single miRNAs to account for their cooperative effects.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2023)
Article
Respiratory System
Monika I. Hollenhorst, Thomas Husnik, Malin Zylka, Nele Duda, Veit Flockerzi, Thomas Tschernig, Stephan Maxeiner, Gabriela Krasteva-Christ
Summary: This study confirmed the presence of tuft cells in the human airway from the trachea to the bronchioles. Tuft cells were found to play a functional role in regulating mucociliary clearance by activating the TRPM5 channel through bitter substances, and involving cholinergic and nitric oxide signaling pathways.
RESPIRATORY RESEARCH
(2023)
Article
Multidisciplinary Sciences
Philipp Wartenberg, Femke Lux, Kai Busch, Claudia Fecher-Trost, Amanda Wyatt, Veit Flockerzi, Gabriela Krasteva-Christ, Ulrich Boehm, Petra Weissgerber
Summary: Transient receptor potential (TRP) ion channels are important in human and mouse biology, and can be potential therapeutic targets in treating disease. This study presents an optimized method to visualize TRP-expressing cells and combines gene expression profiling with mass spectrometry to study protein levels in selected organs. The method can be used for other genes of interest and reporter mice.