8,178 results match your criteria receptor gating


Extracellular cap domain is an essential component of the TRPV1 gating mechanism.

Nat Commun 2021 04 12;12(1):2154. Epub 2021 Apr 12.

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.

Transient receptor potential (TRP) channels are polymodal molecular sensors involved in numerous physiological processes and implicated in a variety of human diseases. Several structures of the founding member of the TRP channel family, TRPV1, are available, all of which were determined for the protein missing the N- and C-termini and the extracellular S5-P-loop. Here, we present structures of the full-length thirteen-lined ground squirrel TRPV1 solved by cryo-EM. Read More

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Pollen PCP-B peptides unlock a stigma peptide-receptor kinase gating mechanism for pollination.

Science 2021 04;372(6538):171-175

School of Life Sciences, East China Normal University, Shanghai, China.

Sexual reproduction in angiosperms relies on precise communications between the pollen and pistil. The molecular mechanisms underlying these communications remain elusive. We established that in , a stigmatic gatekeeper, the ANJEA-FERONIA (ANJ-FER) receptor kinase complex, perceives the RAPID ALKALINIZATION FACTOR peptides RALF23 and RALF33 to induce reactive oxygen species (ROS) production in the stigma papillae, whereas pollination reduces stigmatic ROS, allowing pollen hydration. Read More

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Differential sensitivity of cinnamaldehyde-evoked calcium fluxes to ruthenium red in guinea pig and mouse trigeminal sensory neurons.

BMC Res Notes 2021 Apr 7;14(1):127. Epub 2021 Apr 7.

Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA.

Objective: Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel expressed on a subset of sensory neurons. TRPA1 is activated by a host of noxious stimuli including pollutants, irritants, oxidative stress and inflammation, and is thought to play an important role in nociception and pain perception. TRPA1 is therefore a therapeutic target for diseases with nociceptive sensory signaling components. Read More

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Unmasking coupling between channel gating and ion permeation in the muscle nicotinic receptor.

Elife 2021 04 6;10. Epub 2021 Apr 6.

Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Rochester, United States.

Whether ion channel gating is independent of ion permeation has been an enduring, unresolved question. Here, applying single channel recording to the archetypal muscle nicotinic receptor, we unmask coupling between channel gating and ion permeation by structural perturbation of a conserved intramembrane salt bridge. A charge-neutralizing mutation suppresses channel gating, reduces unitary current amplitude, and increases fluctuations of the open channel current. Read More

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Transcriptome and IgH Repertoire Analyses Show That CD11c B Cells Are a Distinct Population With Similarity to B Cells Arising in Autoimmunity and Infection.

Front Immunol 2021 19;12:649458. Epub 2021 Mar 19.

Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.

A distinct B cell population marked by elevated CD11c expression is found in patients with systemic lupus erythematosus (SLE). Cells with a similar phenotype have been described during chronic infection, but variable gating strategies and nomenclature have led to uncertainty of their relationship to each other. We isolated CD11c cells from peripheral blood and characterized them using transcriptome and IgH repertoire analyses. Read More

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Neuromodulation of Persistent Activity and Working Memory Circuitry in Primate Prefrontal Cortex by Muscarinic Receptors.

Front Neural Circuits 2021 15;15:648624. Epub 2021 Mar 15.

Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada.

Neuromodulation by acetylcholine plays a vital role in shaping the physiology and functions of cerebral cortex. Cholinergic neuromodulation influences brain-state transitions, controls the gating of cortical sensory stimulus responses, and has been shown to influence the generation and maintenance of persistent activity in prefrontal cortex. Here we review our current understanding of the role of muscarinic cholinergic receptors in primate prefrontal cortex during its engagement in the performance of working memory tasks. Read More

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Flexible scaling and persistence of social vocal communication.

Nature 2021 Mar 31. Epub 2021 Mar 31.

Department of Neuroscience, Scripps Research, La Jolla, CA, USA.

Innate vocal sounds such as laughing, screaming or crying convey one's feelings to others. In many species, including humans, scaling the amplitude and duration of vocalizations is essential for effective social communication. In mice, female scent triggers male mice to emit innate courtship ultrasonic vocalizations (USVs). Read More

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Antiviral Drug Ivermectin at Nanomolar Concentrations Inhibits Glycine-Induced Chloride Current in Rat Hippocampal Neurons.

Bull Exp Biol Med 2021 Mar 31;170(5):649-653. Epub 2021 Mar 31.

Research Center of Neurology, Moscow, Russia.

Ivermectin (IVM) belongs to the class of macrocyclic lactones, which is used as an antiparasitic agent. At present, the researchers focus on possibility to use IVM in treatment of certain forms of cancer and viral diseases such as COVID-19. The mechanisms of IVM action are not clear. Read More

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Signal transduction through Cys-loop receptors is mediated by the nonspecific bumping of closely apposed domains.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;

One of the most fundamental questions in the field of Cys-loop receptors (pentameric ligand-gated ion channels, pLGICs) is how the affinity for neurotransmitters and the conductive/nonconductive state of the transmembrane pore are correlated despite the ∼60-Å distance between the corresponding domains. Proposed mechanisms differ, but they all converge into the idea that interactions between wild-type side chains across the extracellular-transmembrane-domain (ECD-TMD) interface are crucial for this phenomenon. Indeed, the successful design of fully functional chimeras that combine intact ECD and TMD modules from different wild-type pLGICs has commonly been ascribed to the residual conservation of sequence that exists at the level of the interfacial loops even between evolutionarily distant parent channels. Read More

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Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time.

J Vis Exp 2021 Mar 11(169). Epub 2021 Mar 11.

Department of Physiology, Anatomy and Genetics, University of Oxford; Department of Chemistry and Neuroscience Program, Trinity College;

We have developed a method to measure binding of adenine nucleotides to intact, functional transmembrane receptors in a cellular or membrane environment. This method combines expression of proteins tagged with the fluorescent non-canonical amino acid ANAP, and FRET between ANAP and fluorescent (trinitrophenyl) nucleotide derivatives. We present examples of nucleotide binding to ANAP-tagged KATP ion channels measured in unroofed plasma membranes and excised, inside-out membrane patches under voltage clamp. Read More

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ADP-Ribosylation Regulates the Signaling Function of IFN-γ.

Front Immunol 2021 8;12:642545. Epub 2021 Mar 8.

Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Murine T cells express the GPI-anchored ADP-ribosyltransferase 2.2 (ARTC2.2) on the cell surface. Read More

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Gating of the capsaicin receptor TRPV1 by UVA-light and oxidants are mediated by distinct mechanisms.

Cell Calcium 2021 Mar 17;96:102391. Epub 2021 Mar 17.

Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany. Electronic address:

Redox-sensitivity is a common property of several transient receptor potential (TRP) ion channels. Oxidants and UVA-light activate TRPV2 by oxidizing methionine pore residues which are conserved in the capsaicin-receptor TRPV1. However, the redox-sensitivity of TRPV1 is regarded to depend on intracellular cysteine residues. Read More

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Natural Zeitgebers Under Temperate Conditions Cannot Compensate for the Loss of a Functional Circadian Clock in Timing of a Vital Behavior in .

J Biol Rhythms 2021 Mar 22:748730421998112. Epub 2021 Mar 22.

Neurobiology and Genetics, Würzburg Insect Research, Theodor-Boveri-Institute, Biocenter, University of Würzburg, Würzburg, Germany.

The adaptive significance of adjusting behavioral activities to the right time of the day seems obvious. Laboratory studies implicated an important role of circadian clocks in behavioral timing and rhythmicity. Yet, recent studies on clock-mutant animals questioned this importance under more naturalistic settings, as various clock mutants showed nearly normal diel activity rhythms under seminatural zeitgeber conditions. Read More

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Structure and gating mechanism of the α7 nicotinic acetylcholine receptor.

Cell 2021 Apr 17;184(8):2121-2134.e13. Epub 2021 Mar 17.

Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

The α7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and in the cholinergic inflammatory pathway. This ligand-gated ion channel assembles as a homopentamer, is exceptionally permeable to Ca, and desensitizes faster than any other Cys-loop receptor. The α7 receptor has served as a prototype for the Cys-loop superfamily yet has proven refractory to structural analysis. Read More

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TRPM3 in Brain (Patho)Physiology.

Front Cell Dev Biol 2021 26;9:635659. Epub 2021 Feb 26.

Laboratory of Cellular and Molecular Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores. Read More

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February 2021

A short isoform of STIM1 confers frequency-dependent synaptic enhancement.

Cell Rep 2021 Mar;34(11):108844

Molecular Biophysics, Saarland University, 66421 Homburg, Germany. Electronic address:

Store-operated Ca-entry (SOCE) regulates basal and receptor-triggered Ca signaling with STIM proteins sensing the endoplasmic reticulum (ER) Ca content and triggering Ca entry by gating Orai channels. Although crucial for immune cells, STIM1's role in neuronal Ca homeostasis is controversial. Here, we characterize a splice variant, STIM1B, which shows exclusive neuronal expression and protein content surpassing conventional STIM1 in cerebellum and of significant abundance in other brain regions. Read More

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Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.

Elife 2021 03 17;10. Epub 2021 Mar 17.

Department of Psychology, University of California San Diego, San Diego, United States.

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyperactivity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively; however, the underlying mechanisms are unknown. Here we show that alcohol-exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Read More

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Relative expansion of CD19-negative very-early normal B-cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR-T cell therapy: implications for flow cytometric detection of minimal residual disease.

Br J Haematol 2021 Mar 14. Epub 2021 Mar 14.

National Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.

CD19-directed treatment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) frequently leads to the downmodulation of targeted antigens. As multicolour flow cytometry (MFC) application for minimal/measurable residual disease (MRD) assessment in BCP-ALL is based on B-cell compartment study, CD19 loss could hamper MFC-MRD monitoring after blinatumomab or chimeric antigen receptor T-cell (CAR-T) therapy. The use of other antigens (CD22, CD10, CD79a, etc. Read More

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Mol Pharmacol 2021 Mar 9. Epub 2021 Mar 9.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, United States of America

NMDA receptors are ligand-gated ion channels that mediate a slow, Ca-permeable component of excitatory synaptic currents. These receptors are involved in several important brain functions, including learning and memory, and have also been implicated in neuropathological conditions and acute CNS injury, which has driven therapeutic interest in their modulation. The EU1794 series of positive and negative allosteric modulators of NMDA receptors has structural determinants of action near the pre-M1 helix that is involved in channel gating. Read More

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Novel RyR2 Mutation (G3118R) Is Associated With Autosomal Recessive Ventricular Fibrillation and Sudden Death: Clinical, Functional, and Computational Analysis.

J Am Heart Assoc 2021 Mar 9;10(6):e017128. Epub 2021 Mar 9.

Heart Institute Hadassah-Hebrew University Medical Center Jerusalem Israel.

Background The cardiac ryanodine receptor type 2 (RyR2) is a large homotetramer, located in the sarcoplasmic reticulum (SR), which releases Ca from the SR during systole. The molecular mechanism underlying Ca sensing and gating of the RyR2 channel in health and disease is only partially elucidated. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1) is the most prevalent syndrome caused by RyR2 mutations. Read More

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The effects of a novel inhibitor of tumor necrosis factor (TNF) alpha on prepulse inhibition and microglial activation in two distinct rodent models of schizophrenia.

Behav Brain Res 2021 May 5;406:113229. Epub 2021 Mar 5.

Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, United States. Electronic address:

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D receptor sensitivity throughout the animal's lifetime. Read More

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Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.

Molecules 2021 Feb 13;26(4). Epub 2021 Feb 13.

Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Juriquilla, Querétaro 76230, Mexico.

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, I, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). Read More

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February 2021

Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice.

J Psychopharmacol 2021 Apr 1;35(4):469-482. Epub 2021 Mar 1.

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Canada.

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. Read More

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Fluoroethylnormemantine, a novel derivative of memantine, facilitates extinction learning without sensorimotor deficits.

Int J Neuropsychopharmacol 2021 Feb 25. Epub 2021 Feb 25.

Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) / New York State Psychiatric Institute (NYSPI), New York, NY, USA.

Background: Memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been approved for use in Alzheimer's disease (AD), but increasing studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair. Read More

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February 2021

A glycan gate controls opening of the SARS-CoV-2 spike protein.

bioRxiv 2021 Feb 16. Epub 2021 Feb 16.

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded (down) to an exposed (up) state in order to bind the human ACE2 receptor and infect cells. While snapshots of the up and down states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 200 μs of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Read More

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February 2021

The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons.

Front Pharmacol 2021 2;12:632711. Epub 2021 Feb 2.

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, United States.

Transient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its binding sites in the pore region. Read More

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February 2021

Histamine H receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice.

Nat Commun 2021 02 18;12(1):1142. Epub 2021 Feb 18.

Institute of Pharmacology & Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H receptor (HR) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of HR gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. Read More

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February 2021

A critical residue in the αM2-M3 linker regulating mammalian GABA receptor pore gating by diazepam.

Elife 2021 Feb 16;10. Epub 2021 Feb 16.

University of Texas at Austin, Department of Neuroscience, Austin, United States.

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that modulate activity of GABA receptors (GABARs), neurotransmitter-gated ion channels critical for synaptic transmission. However, the physical basis of this modulation is poorly understood. We explore the role of an important gating domain, the αM2-M3 linker, in linkage between the BZD site and pore gate. Read More

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February 2021

Mechanism of gating and partial agonist action in the glycine receptor.

Cell 2021 Feb 9;184(4):957-968.e21. Epub 2021 Feb 9.

Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:

Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Read More

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February 2021

Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis.

Transl Psychiatry 2021 Feb 8;11(1):114. Epub 2021 Feb 8.

Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, 78229, USA.

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. Read More

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February 2021