Article
Immunology
Tehila Mizrachi, Oshrit Marsha, Karen Brusin, Yael Ben-David, Ganesh A. Thakur, Adi Vaknin-Dembinsky, Millet Treinin, Talma Brenner
Summary: GAT107, an ago-PAM of alpha 7 nAChR, can significantly reduce disease severity and neuroinflammation in EAE by activating the receptor, leading to decreased pro-inflammatory cytokine production and increased anti-inflammatory cytokine IL-10. It also alters the expression of immune cell markers and directly activates alpha 7 nAChR in immune cells of MS patients and healthy donors.
JOURNAL OF NEUROINFLAMMATION
(2021)
Article
Cell Biology
Sydney V. Doss, Sebastien Barbat-Artigas, Mikayla Lopes, Bhola Shankar Pradhan, Tomasz J. Proszynski, Richard Robitaille, Gregorio Valdez
Summary: Lynx1 is expressed in skeletal muscles and concentrates at NMJs. It interacts with muscle-specific nAChR subunits and affects the response of skeletal muscles to cholinergic transmission and their contractile properties. Loss of Lynx1 has a minor role in the structural development of NMJs and may primarily function to maintain the structure and function of adult and aging NMJs.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Anna Lauriello, Quinn McVeigh, Rou-Jia Sung
Summary: Ly6 proteins, a large family of prototoxin-like molecules endogenous to mammals, have been implicated in regulating cell signaling processes. This study investigated the possibility of lypd2 as a regulator of AMPAR function and found that there was no interaction between lypd2 and specific isoforms of GluR2, highlighting the importance of further investigating novel targets for Ly6 interaction and regulation.
Article
Biochemistry & Molecular Biology
Yann S. Mineur, Tenna N. Mose, Kathrine Lefoli Maibom, Steven T. Pittenger, Alexa R. Soares, Hao Wu, Seth R. Taylor, Yaqing Huang, Marina R. Picciotto
Summary: The balance between excitatory and inhibitory signaling in the brain is crucial for maintaining homeostatic function. Acetylcholine (ACh) signaling in the basolateral amygdala (BLA) has been found to influence stress-sensitive behaviors by altering the balance of activity among different types of neurons. These findings suggest that ACh modulates the GABAergic signaling network in the BLA, leading to changes in coping strategies during stress.
MOLECULAR PSYCHIATRY
(2022)
Article
Pharmacology & Pharmacy
Victoria R. Sanders, Neil S. Millar
Summary: Considerable progress has been made in the identification and characterization of subtype-selective modulators of nicotinic acetylcholine receptors (nAChRs), specifically alpha 7 nAChRs. This review focuses on alpha 7-selective modulators that bind to receptor sites other than the orthosteric agonist binding site for acetylcholine. The mechanism of action and binding sites of these modulators is still a topic of debate.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Miquel Saumell-Esnaola, Sergio Barrondo, Gontzal Garcia del Cano, Maria Aranzazu Goicolea, Joan Salles, Beat Lutz, Krisztina Monory
Summary: This study investigated the role of CB1 receptor in glutamatergic and GABAergic neurons and its signaling properties, showing that the coupling of CB1 receptor to Gαi/o proteins is correlated with CB1 receptor abundance in different cell types. The results provide a new perspective on the functional coupling of CB1 receptor at excitatory and inhibitory terminals, highlighting the utility of the CB1 rescue model in studying endocannabinoid physiology at the subcellular level.
Article
Biochemistry & Molecular Biology
Qimeng Li, Akos Nemecz, Gabriel Ayme, Gabrielle Dejean de la Batie, Marie S. Prevost, Stephanie Pons, Nathalie Barilone, Rayen Baachaoui, Uwe Maskos, Pierre Lafaye, Pierre-Jean Corringer
Summary: Two single-domain antibody fragments, C4 and E3, have been found to bind to the α7-nAChR and have different functional properties, indicating the importance of the extracellular site.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Mahip K. Verma, Rajan N. Goel, Anand M. Bokare, Manoj P. Dandekar, Sarita Koul, Sagar Desai, Santoshkumar Tota, Nilendra Singh, Prashant B. Nigade, Vinod B. Patil, Dipak Modi, Maneesh Mehta, Jayasagar Gundu, Sameer S. Walunj, Navnath P. Karche, Neelima Sinha, Rajender K. Kamboj, Venkata P. Palle
Summary: The study introduces a novel alpha 7 nAChR positive allosteric modulator (PAM), LL-00066471, which shows excellent oral bioavailability and potential in symptomatically alleviating cognitive deficits and sensorimotor gating deficits.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Sophie Shi, Solene N. Lefebvre, Laurie Peverini, Adrien H. Cerdan, Paula Milan Rodriguez, Marc Gielen, Jean-Pierre Changeux, Marco Cecchini, Pierre-Jean Corringer
Summary: This study investigates the gating mechanism of the glycine receptor through voltage-clamp fluorometry (VCF). Fluorescence reports a glycine-induced conformational change that occurs before pore opening. Molecular dynamic simulations show the dynamic nature of a partial agonist bound-closed Cryo-EM structure, generating docking properties that recapitulate the VCF data. This research reveals the progressive propagating transition towards channel opening and highlights the structural plasticity within the mechanism of action of allosteric effectors.
NATURE COMMUNICATIONS
(2023)
Article
Neurosciences
B. T. Kipp, P. T. Nunes, E. Galaj B. Hitchcock, T. Nasra, K. R. Poynor, S. K. Heide, N. L. Reitz, L. M. Savage
Summary: During adolescence, heavy binge-like ethanol consumption can lead to structural and functional impairments in the frontocortical region, disrupting the normal development of the cholinergic circuit. Adolescent intermittent ethanol exposure induces cholinergic dysfunction, but performance on spatial memory task and operant reversal task remains unaltered.
Article
Biochemistry & Molecular Biology
Olga Abramova, Yana Zorkina, Timur Syunyakov, Eugene Zubkov, Valeria Ushakova, Artemiy Silantyev, Kristina Soloveva, Olga Gurina, Alexander Majouga, Anna Morozova, Vladimir Chekhonin
Summary: The study found that ultrasound stress can lead rats to exhibit depressive-like behavior, while treatment with clomipramine can have an antidepressant effect. Different routes of drug administration can influence the drug's impact on the metabolic profiles in the frontal cortex and hippocampus.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Domenico Pimpinella, Valentina Mastrorilli, Corinna Giorgi, Silke Coemans, Salvatore Lecca, Arnaud L. Lalive, Hannah Ostermann, Elke C. Fuchs, Hannah Monyer, Andrea Mele, Enrico Cherubini, Marilena Griguoli
Summary: Acetylcholine (ACh) in the hippocampus plays a crucial role in social memory by controlling social novelty discrimination in mice. The activation of nicotinic ACh receptors (nAChRs) in the CA2 region enhances the excitatory drive to principal cells and affects social novelty discrimination. Optogenetic activation of cholinergic neurons in the medial septum/diagonal band of Broca (MSDB) increases the firing of CA2 principal cells, highlighting nAChRs as essential players in this process.
Article
Multidisciplinary Sciences
Elisa N. Falk, Kevin J. Norman, Yury Garkun, Michael P. Demars, Susanna Im, Giulia Taccheri, Jenna Short, Keaven Caro, Sarah E. McCraney, Christina Cho, Milo R. Smith, Hung-Mo Lin, Hiroyuki Koike, Julia Bateh, Priscilla Maccario, Leah Waltrip, Meaghan Janis, Hirofumi Morishita
Summary: This study reveals that dynamic regulation of the nicotinic cholinergic system plays a key role in the maturation of attentional circuit, particularly in the development of top-down frontal neurons. Following adolescence, the decrease in nicotinic tone by upregulation of Lynxl promotes the establishment of attentional behavior in adulthood. Disruption of this key maturational process is observed in a mouse model of fragile X syndrome, but can be rescued by suppressing nicotinic tone through the introduction of Lynxl in top-down projections.
Article
Pharmacology & Pharmacy
Risa Okimoto, Katsutoshi Ino, Kenichiro Ishizu, Hajime Takamatsu, Kazuyuki Sakamoto, Hironori Yuyama, Hideyoshi Fuji, Akiyoshi Someya, Akiyoshi Ohtake, Takao Ishigami, Noriyuki Masuda, Masahiro Takeda, Shunichi Kajioka, Naoki Yoshimura
Summary: The novel M-3 receptor positive allosteric modulator ASP8302 enhances human M-3 receptor activation by interacting with a residue distinct from reported allosteric sites, suggesting not only a novel allosteric site of M-3 receptors but also potential application in diseases caused by insufficient M-3 receptor activation. This finding provides significant insight into further research on the allosteric modulation mechanism of M-3 and other muscarinic receptors.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Article
Chemistry, Medicinal
Madeline F. Long, Rory A. Capstick, Paul K. Spearing, Julie L. Engers, Alison R. Gregro, Sean R. Bollinger, Sichen Chang, Vincent B. Luscombe, Alice L. Rodriguez, Hyekyung P. Cho, Colleen M. Niswender, Thomas M. Bridges, P. Jeffrey Conn, Craig W. Lindsley, Darren W. Engers, Kayla J. Temple
Summary: The Letter details efforts to develop novel tricyclic M-4 PAM scaffolds with improved pharmacological properties. A tie-back strategy was employed to replace the core structure, leading to the discovery of two novel tricyclic cores with low nanomolar potency against the human M-4 receptor.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Anne-Marie Lundsgaard, Andreas M. Fritzen, Trine S. Nicolaisen, Christian S. Carl, Kim A. Sjoberg, Steffen H. Raun, Anders B. Klein, Eva Sanchez-Quant, Jakob Langer, Cathrine Orskov, Christoffer Clemmensen, Matthias H. Tschoep, Erik A. Richter, Bente Kiens, Maximillian Kleinert
JOURNAL OF LIPID RESEARCH
(2020)
Article
Endocrinology & Metabolism
Sigrid Jall, Meri De Angelis, Anne-Marie Lundsgaard, Andreas M. Fritzen, Trine S. Nicolaisen, Anders B. Klein, Aaron Novikoff, Stephan Sachs, Erik A. Richter, Bente Kiens, Karl-Werner Schramm, Matthias H. Tschoep, Kerstin Stemmer, Christoffer Clemmensen, Timo D. Mueller, Maximilian Kleinert
Article
Biochemistry & Molecular Biology
Trine S. Nicolaisen, Anders B. Klein, Oksana Dmytriyeva, Jens Lund, Lars R. Ingerslev, Andreas M. Fritzen, Christian S. Carl, Anne-Marie Lundsgaard, Mikkel Frost, Tao Ma, Peter Schjerling, Zachary Gerhart-Hines, Frederic Flamant, Karine Gauthier, Steen Larsen, Erik A. Richter, Bente Kiens, Christoffer Clemmensen
Article
Multidisciplinary Sciences
Anders B. Klein, Trine S. Nicolaisen, Niels Ortenblad, Kasper D. Gejl, Rasmus Jensen, Andreas M. Fritzen, Emil L. Larsen, Kristian Karstoft, Henrik E. Poulsen, Thomas Morville, Ronni E. Sahl, Jorn W. Helge, Jens Lund, Sarah Falk, Mark Lyngbaek, Helga Ellingsgaard, Bente K. Pedersen, Wei Lu, Brian Finan, Sebastian B. Jorgensen, Randy J. Seeley, Maximilian Kleinert, Bente Kiens, Erik A. Richter, Christoffer Clemmensen
Summary: Prolonged endurance exercise increases circulating GDF15 levels in humans to levels observed in pathophysiological conditions, but this exercise-induced GDF15 does not affect post-exercise food intake or exercise motivation like pharmacological GDF15 does.
NATURE COMMUNICATIONS
(2021)
Article
Dermatology
Mikhail A. Shulepko, Maxim L. Bychkov, Zakhar O. Shenkarev, Dmitrii S. Kulbatskii, Alexey M. Makhonin, Alexander S. Paramonov, Anton O. Chugunov, Mikhail P. Kirpichnikov, Ekaterina N. Lyukmanova
Summary: Mal de Meleda is a palmoplantar keratoderma associated with mutations in the SLURP-1 gene, which controls the growth, differentiation, and apoptosis of keratinocytes. Mutations in different regions of SLURP-1 have varying effects on its antiproliferative activity against keratinocytes. This study provides insights into the functional and structural implications of SLURP-1 mutations in the pathogenesis of Mal de Meleda.
JOURNAL OF INVESTIGATIVE DERMATOLOGY
(2021)
Article
Biochemistry & Molecular Biology
M. Yu. Myshkin, A. S. Paramonov, D. S. Kulbatskii, E. A. Surkova, A. A. Berkut, A. A. Vassilevski, E. N. Lyukmanova, M. P. Kirpichnikov, Z. O. Shenkarev
Summary: Voltage-gated sodium channels have modular architecture with five membrane domains, where peripheral voltage-sensing domains are responsible for channel activation and rapid inactivation. Gating modifier toxins from arthropod venoms interact with these domains, potentially serving as prototypes for new drugs. In this study, the toxin Hm-3 showed high affinity to VSD-III of human skeletal muscle Na(V)1.4 channel, with specific residues likely interacting with the channel and the lipid bilayer.
Article
Multidisciplinary Sciences
Ulrike Leurs, Anders B. Klein, Ethan D. McSpadden, Nane Griem-Krey, Sara M. O. Solbak, Josh Houlton, Inge S. Villumsen, Stine B. Vogensen, Louise Hamborg, Stine J. Gauger, Line B. Palmelund, Anne Sofie G. Larsen, Mohamed A. Shehata, Christian D. Kelstrup, Jesper Olsen, Anders Bach, Robert O. Burnie, D. Steven Kerr, Emma K. Gowing, Selina M. W. Teurlings, Chris C. Chi, Christine L. Gee, Bente Frolund, Birgitte R. Kornum, Geeske M. van Woerden, Rasmus P. Clausen, John Kuriyan, Andrew N. Clarkson, Petrine Wellendorph
Summary: This study demonstrates the selective binding of compounds related to GHB to CaMKIIα, leading to increased thermal stability of the hub and providing neuroprotection, particularly under pathological conditions. This unexpected interaction establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Neurosciences
Altair B. Dos Santos, Line K. Skaanning, Eyd Mikkelsen, Cesar R. Romero-Leguizamon, Morten P. Kristensen, Anders B. Klein, Siganya Thaneshwaran, Annette E. Langkilde, Kristi A. Kohlmeier
Summary: In summary, the study found that both monomeric and fibril forms of alpha-synuclein induced excitement and increased calcium in laterodorsal tegmentum and pedunculopontine tegmentum neurons, while the monomeric form heightened neuronal death. In substantia nigra, alpha-synuclein displayed inhibitory effects, decreased intracellular calcium, and monomeric form was not associated with heightened cell death. The nucleus-specific differential effects suggest potential mechanisms underlying sleep disorders' prodromal appearance in Parkinson's disease.
JOURNAL OF PARKINSONS DISEASE
(2021)
Article
Cell Biology
Maxim L. Bychkov, Mikhail A. Shulepko, Olga Shlepova, Dmitrii S. Kulbatskii, Irina A. Chulina, Alexander S. Paramonov, Ludmila K. Baidakova, Viatcheslav N. Azev, Sergey G. Koshelev, Mikhail P. Kirpichnikov, Zakhar O. Shenkarev, Ekaterina N. Lyukmanova
Summary: SLURP-1 inhibits proliferation and migration of A549 lung adenocarcinoma cells by reducing phosphorylation levels in the PI3K/AKT/mTOR signaling pathway and affecting the activity of PDGFR and EGFR. Furthermore, SLURP-1 also suppresses migration of A549 cells and forms complexes with various cell membrane receptors.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Dmitrii Kulbatskii, Zakhar Shenkarev, Maxim Bychkov, Eugene Loktyushov, Mikhail Shulepko, Sergey Koshelev, Igor Povarov, Alexander Popov, Steve Peigneur, Anton Chugunov, Sergey Kozlov, Irina Sharonova, Roman Efremov, Vladimir Skrebitsky, Jan Tytgat, Mikhail Kirpichnikov, Ekaterina Lyukmanova
Summary: Lypd6 is a GPI-tethered protein in the Ly-6/uPAR family that enhances Wnt/beta-catenin signaling and has been suggested to affect nicotinic acetylcholine receptors (nAChRs). The recombinant water-soluble variant of Lypd6 inhibits ACh-evoked currents at α3β4- and α7-nAChRs, and can also suppress long-term potentiation in mouse hippocampal slices. Colocalization of Lypd6 with nAChRs was observed in primary cortical and hippocampal neurons, indicating its role in cholinergic system regulation in the brain.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Alexander S. Paramonov, Ekaterina N. Lyukmanova, Alexander G. Tonevitsky, Alexander S. Arseniev, Zakhar O. Shenkarev
Summary: Thionins are small cationic cysteine-rich peptides involved in plant immune response, with Viscotoxin A3 (VtA3) from mistletoe demonstrating antimicrobial and cytotoxic activity. The structure of VtA3 in membrane-mimicking media was studied, showing stability and potential ion channel formation. VtA3 interacts with membranes and can form oligomers in certain conditions, with potential implications for membrane disruption mechanisms.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Maxim L. Bychkov, Artem V. Kirichenko, Mikhail A. Shulepko, Irina N. Mikhaylova, Mikhail P. Kirpichnikov, Ekaterina N. Lyukmanova
Summary: Extracellular acidification promotes proliferation, migration, and invasion of metastatic melanoma cells, but has no effect on normal keratinocytes. The use of ASIC1a inhibitor mambalgin-2 can suppress these processes and induce apoptosis in melanoma cells. Targeting ASIC1a with drugs like mambalgin-2 could be a promising strategy for metastatic melanoma treatment.
Article
Endocrinology & Metabolism
Stephanie Holm, Anna S. Husted, Louise J. Skov, Thomas H. Morville, Christoffer A. Hagemann, Tina Jorsal, Morten Dall, Alexander Jakobsen, Anders B. Klein, Jonas T. Treebak, Filip K. Knop, Thue W. Schwartz, Christoffer Clemmensen, Birgitte Holst
Summary: This study found that LEAP2 is downregulated during states of energy deprivation in both humans and rodents. The recovery period after endurance exercise is associated with increased levels of BHB and decreased levels of LEAP2 in humans. In fasting and ketogenic diet conditions, Leap2 expression in the liver is decreased. Furthermore, oral administration of BHB and direct exposure to BHB in hepatocytes also decrease LEAP2 levels.
Article
Psychiatry
Nicole Fadahunsi, Jens Lund, Alberte Wollesen Breum, Cecilie Vad Mathiesen, Isabella Beck Larsen, Gitte Moos Knudsen, Anders Bue Klein, Christoffer Clemmensen
Summary: The effects of psilocybin on feeding behavior and energy metabolism in mice were evaluated. It was found that psilocybin had no significant effects on food intake and body weight. A single dose of psilocybin had a substantial impact on the prefrontal cortex transcriptome but did not alter the diet-induced obese mice's feeding behavior and body weight.
TRANSLATIONAL PSYCHIATRY
(2022)
Article
Cell Biology
Anders B. Klein, Trine S. Nicolaisen, Kornelia Johann, Andreas M. Fritzen, Cecilie Mathiesen, Claudia Gil, Nanna S. Pilmark, Kristian Karstoft, Martin B. Blond, Jonas S. Quist, Randy J. Seeley, Kristine Faerch, Jens Lund, Maximilian Kleinert, Christoffer Clemmensen
Summary: Metformin has been widely used, but the mechanism of its weight loss effect is not fully understood. This study confirms that metformin can increase the levels of GDF15 in the body, but the role of the GDF15-GFRAL pathway in mediating the weight loss effect of metformin remains controversial. The results suggest that the effects of metformin on energy balance may not solely depend on the GDF15-GFRAL pathway.