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481 results on '"Jayaraman, Vasanthi"'

104. Mechanism-based discovery of ligands that counteract inhibition of the nicotinic acetylcholine receptor by cocaine and MK-801

Author

Hess, George P., Ulrich, Henning, Breitinger, Hans-Georg, Niu, Li, Gameiro, Armanda M., Grewer, Christof, Srivastava, Sanjay, Ippolito, Joseph E., Lee, Sean M., Jayaraman, Vasanthi, and Coombs, Susan E.

Subjects
Nicotinic receptors -- Research, Acetylcholine -- Research, Ligands -- Research, Nervous system -- Research, Cocaine -- Research, Cell research -- Analysis, Science and technology
Abstract

Nicotinic acetylcholine receptors (AChR) belong to a family of proteins that form ligand-gated transmembrane ion channels. They are involved in the fast transmission of signals between cells and the control of intercellular communication in the nervous system. A variety of therapeutic agents and abused drugs, including cocaine, inhibit the AChR and monoamine transporters and interfere with nervous system function. Here we describe a mechanism-based approach to prevent this inhibition. We had previously developed presteady-state kinetic (transient kinetic) techniques, with microsecond-to-millisecond time resolutions, for investigations of reactions on cell surfaces that allow one to determine the effects of inhibitors not only on the channel-opening probability but also on the opening and closing rates of the AChR channel. The transient kinetic measurements led to two predictions. (i) Ligands that bind to a regulatory site on the closed-channel conformation of the AChR with higher affinity than to the site on the open-channel form shift the equilibrium toward the closed-channel form, thereby inhibiting the receptor. (ii) Ligands that bind to a regulatory site with an affinity for the open conformation equal to or higher than their affinity for the closed conformations are expected not to inhibit the receptor and to displace inhibitors. The identification of such ligands in a combinatorial library of RNA ligands is reported. The implication of this approach to other protein-mediated reactions in which an inhibitor changes the equilibrium between active and inactive conformations is discussed.

Published
2000

105. AMPA Receptor Modulation by Stargazin

Author

Shaikh, Sana A., primary, Dolino, Drew M., additional, Lee, Garam, additional, Chatterjee, Sudeshna, additional, MacLean, David M., additional, Flatebo, Charlotte, additional, Landes, Christy F., additional, and Jayaraman, Vasanthi, additional

Published
2017
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112. Stargazin Modulation of AMPA Receptors

Author

Shaikh, Sana A., primary, Dolino, Drew M., additional, Lee, Garam, additional, Chatterjee, Sudeshna, additional, MacLean, David M., additional, Flatebo, Charlotte, additional, Landes, Christy F., additional, and Jayaraman, Vasanthi, additional

Published
2016
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121. Photolysis of gamma-(alpha-carboxy-2-nitrobenzyl)-L-glutamic acid investigated in the microsecond time scale by time-resolved FTIR

Author

Cheng, Qing, Steinmetz, Mark G., and Jayaraman, Vasanthi

Subjects
Photomechanical processes -- Analysis, Spectrum analysis -- Research, Fourier transform spectroscopy -- Usage, Inorganic compounds -- Research, Chemistry
Abstract

Measurement of the release of substrate from the photolysis of the caged glutamate derivative in aqueous medium, in the microsecond time scale, is presented using Fourier transform infrared of gamma-(alpha-carboxy-2-nitrobenzyl)-L-glutamate.

Published
2002

139. The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions

Author

Chen, Jinjun, Li, Lingyong, Chen, Shao-Rui, Chen, Hong, Xie, Jing-Dun, Sirrieh, Rita E., MacLean, David M., Zhang, Yuhao, Zhou, Meng-Hua, Jayaraman, Vasanthi, and Pan, Hui-Lin

Abstract

α2δ-1, commonly known as a voltage-activated Ca2+channel subunit, is a binding site of gabapentinoids used to treat neuropathic pain and epilepsy. However, it is unclear how α2δ-1 contributes to neuropathic pain and gabapentinoid actions. Here, we show that Cacna2d1overexpression potentiates presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons to cause pain hypersensitivity. Conversely, Cacna2d1knockdown or ablation normalizes synaptic NMDAR activity increased by nerve injury. α2δ-1 forms a heteromeric complex with NMDARs in rodent and human spinal cords. The α2δ-1-NMDAR interaction predominantly occurs through the C terminus of α2δ-1 and promotes surface trafficking and synaptic targeting of NMDARs. Gabapentin or an α2δ-1 C terminus-interfering peptide normalizes NMDAR synaptic targeting and activity increased by nerve injury. Thus, α2δ-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery in neuropathic pain. Gabapentinoids reduce neuropathic pain by inhibiting forward trafficking of α2δ-1-NMDAR complexes.

Published
2018
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140. Dual Effects of TARP γ-2 on Glutamate Efficacy Can Account for AMPA Receptor Autoinactivation

Author

Coombs, Ian D., MacLean, David M., Jayaraman, Vasanthi, Farrant, Mark, and Cull-Candy, Stuart G.

Abstract

Fast excitatory transmission in the CNS is mediated mainly by AMPA-type glutamate receptors (AMPARs) associated with transmembrane AMPAR regulatory proteins (TARPs). At the high glutamate concentrations typically seen during synaptic transmission, TARPs slow receptor desensitization and enhance mean channel conductance. However, their influence on channels gated by low glutamate concentrations, as encountered during delayed transmitter clearance or synaptic spillover, is poorly understood. We report here that TARP γ-2 reduces the ability of low glutamate concentrations to cause AMPAR desensitization and enhances channel gating at low glutamate occupancy. Simulations show that, by shifting the balance between AMPAR activation and desensitization, TARPs can markedly facilitate the transduction of spillover-mediated synaptic signaling. Furthermore, the dual effects of TARPs can account for biphasic steady-state glutamate concentration-response curves—a phenomenon termed “autoinactivation,” previously thought to reflect desensitization-mediated AMPAR/TARP dissociation.

Published
2017
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150. Dynamic membrane protein topological switching upon changes in phospholipid environment.

Author

Vitrac, Heidi, MacLean, David M., Jayaraman, Vasanthi, Bogdanov, Mikhail, and Dowhan, William

Subjects
MEMBRANE proteins, TOPOLOGY, PROTEIN-lipid interactions, PHOSPHOLIPIDS, LIPIDS
Abstract

A fundamental objective in membrane biology is to understand and predict how a protein sequence folds and orients in a lipid bilayer. Establishing the principles governing membrane protein folding is central to understanding the molecular basis formembrane proteins that display multiple topologies, the intrinsic dynamic organization of membrane proteins, and membrane protein conformational disorders resulting in disease. We previously established that lactose permease of Escherichia coli displays a mixture of topological conformations and undergoes postassembly bidirectional changes in orientation within the lipid bilayer triggered by a change in membrane phosphatidylethanolamine content, both in vivo and in vitro. However, the physiological implications and mechanism of dynamic structural reorganization of membrane proteins due to changes in lipid environment are limited by the lack of approaches addressing the kinetic parameters of transmembrane protein flipping. In this study, real-time fluorescence spectroscopy was used to determine the rates of protein flipping in the lipid bilayer in both directions and transbilayer flipping of lipids triggered by a change in proteoliposome lipid composition. Our results provide, for the first time to our knowledge, a dynamic picture of these events and demonstrate that membrane protein topological rearrangements in response to lipid modulations occur rapidly following a threshold change in proteoliposome lipid composition. Protein flipping was not accompanied by extensive lipid-dependent unfolding of transmembrane domains. Establishment of lipid bilayer asymmetry was not required but may accelerate the rate of protein flipping. Membrane protein flipping was found to accelerate the rate of transbilayer flipping of lipids. [ABSTRACT FROM AUTHOR]

Published
2015
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