Auxiliary proteins promote modal gating of <scp>AMPA</scp>‐ and kainate‐type glutamate receptors

Zhang, Wei; Devi, Suma Priya Sudarsana; Tomita, Susumu; Howe, James R.

doi:10.1111/ejn.12519

Cited by 54 publications

(103 citation statements)

References 63 publications

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“…A saturating concentration of JNJ-55511118 reduces peak responses by 36-44%, and steadystate currents by ∼75%. This reduction is consistent with masking the increases in single-channel conductance observed in studies of single-channel kinetics of TARPed versus TARP-less AMPA receptors (Shelley et al, 2012;Zhang et al, 2014). This inhibition is accompanied by an increase in the desensitization and deactivation kinetic rates.…”

Section: Discussionsupporting

confidence: 82%

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8

Maher

Ravula

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

153

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Members of the a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein g8 (TARP-g8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-g8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets.

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Section: Discussionsupporting

confidence: 82%

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8

Maher

Ravula

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

153

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“…1C; fig. S2), as expected (26–30). Thus, the presence of the GT linker between GluA2 and STZ in our GluA2-STZ construct did not significantly affect modulation of GluA2 function by STZ.…”

supporting

confidence: 85%

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

Twomey

Yelshanskaya

Grassucci

et al. 2016

Science

122

189

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AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission, and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo-EM to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2 or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR. Analysis of the AMPAR-STZ binding interfaces suggests that electrostatic interactions between the extracellular domains of AMPAR and STZ play an important role in modulating AMPAR function through contact surfaces that are conserved across AMPARs and TARPs. We propose a model explaining how TARPs stabilize the activated state of AMPARs and how the interactions between AMPARs and their auxiliary proteins control fast excitatory synaptic transmission.

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“…Single-channel studies have shown that AMPARs open to various distinct subconductance states (Wyllie et al, 1993;Swanson et al, 1997) thought to reflect the number of subunits individually activated (Rosenmund et al, 1998;Smith and Howe, 2000;Gebhardt and Cull-Candy, 2006). Thus, an increased mean conductance could reflect an increase in the proportion of openings to the larger subconductance states-altered gating-or an increase in the conductance of all states (altered permeation; Tomita et al, 2005;Shelley et al, 2012;Zhang et al, 2014). Our present data do not allow us to distinguish between these two possibilities.…”

Section: Role Of the C-tail Of ␥-2 In Ampar Functionmentioning

confidence: 56%

Molecular Mechanisms Contributing to TARP Regulation of Channel Conductance and Polyamine Block of Calcium-Permeable AMPA Receptors

et al. 2014

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Many properties of fast synaptic transmission in the brain are influenced by transmembrane AMPAR regulatory proteins (TARPs) that modulate the pharmacology and gating of AMPA-type glutamate receptors (AMPARs). Although much is known about TARP influence on AMPAR pharmacology and kinetics through their modulation of the extracellular ligand-binding domain (LBD), less is known about their regulation of the ion channel region. TARP-induced modifications in AMPAR channel behavior include increased single-channel conductance and weakened block of calcium-permeable AMPARs (CP-AMPARs) by endogenous intracellular polyamines. To investigate how TARPs modify ion flux and channel block, we examined the action of ␥-2 (stargazin) on GluA1 and GluA4 CP-AMPARs. First, we compared the permeation of organic cations of different sizes. We found that ␥-2 increased the permeability of several cations but not the estimated AMPAR pore size, suggesting that TARP-induced relief of polyamine block does not reflect altered pore diameter. Second, to determine whether residues in the TARP intracellular C-tail regulate polyamine block and channel conductance, we examined various ␥-2 C-tail mutants. We identified the membrane proximal region of the C terminus as crucial for full TARP-attenuation of polyamine block, whereas complete deletion of the C-tail markedly enhanced the TARP-induced increase in channel conductance; thus, the TARP C-tail influences ion permeation. Third, we identified a site in the pore-lining region of the AMPAR, close to its Q/R site, that is crucial in determining the TARP-induced changes in single-channel conductance. This conserved residue represents a site of TARP action, independent of the AMPAR LBD.

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Auxiliary proteins promote modal gating of AMPA‐ and kainate‐type glutamate receptors

Cited by 54 publications

References 63 publications

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8

Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

Molecular Mechanisms Contributing to TARP Regulation of Channel Conductance and Polyamine Block of Calcium-Permeable AMPA Receptors

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