Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits

Tomita, Susumu

doi:10.1152/physiol.00033.2009

Cited by 55 publications

(56 citation statements)

References 98 publications

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“…TARP co-expression is associated with reduced desensitization and enhanced steady-state AMPAR currents (Jackson and Nicoll, 2011; Tomita, 2010). To test for a role of TARPs in the slow EPSC we recorded EPSCs in UBCs from stargazer ( stg ) mice, which lack γ2 TARP (Letts et al, 1998), comparing their amplitudes to those of wildtype (wt) mice.…”

Section: Resultsmentioning

confidence: 99%

Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters

Balmer

Romero

et al. 2017

Neuron

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Summary AMPARs mediate the briefest synaptic currents in the brain by virtue of their rapid gating kinetics. However, at the mossy fiber-to-unipolar brush cell synapse in the cerebellum, AMPAR-mediated EPSCs last for hundreds of milliseconds, and it has been proposed that this time course reflects slow diffusion from a complex synaptic space. We show that upon release of glutamate, synaptic AMPARs were desensitized by transmitter by >90%. As glutamate levels subsequently fell, recovery of transmission occurred due to the presence of the AMPAR accessory protein stargazin that enhances the AMPAR response to low levels of transmitter. This gradual increase in receptor activity following desensitization accounted for the majority of synaptic transmission at this synapse. Moreover, the amplitude, duration and shape of the synaptic response was tightly controlled by plasma membrane glutamate transporters, indicating that clearance of synaptic glutamate during the slow EPSC is dictated by an uptake process.

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Section: Resultsmentioning

confidence: 99%

Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters

Balmer

Romero

et al. 2017

Neuron

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“…Excitatory ionotropic glutamate receptors are important controllers of excitatory neurotransmission, neuronal firing and brain metabolism Fowler et al, 2004;Tomita, 2010). They are also associated with learning and memory (Fowler et al, 2004;Zeng et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Reduced effect of stimulation of AMPA receptors on cerebral O2 consumption in a rat model of autism

Weiss¹,

Liu

Grewal

et al. 2012

Neuropharmacology

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“…Receptor functional heterogeneity is expanded through RNA splicing and RNA editing and through differential assembly with auxiliary accessory transmembrane proteins and cytoplasmic proteins that interact with the carboxyl terminus (Tomita, 2010). Each subunit is composed of four domains: an amino-terminal domain, a ligand-binding core or domain (LBC or LBD) to which both agonists and allosteric modulators bind, the membrane spanning domains (M1, M3, and M4) and a re-entrant pore loop (M2), and the cytoplasmic domain.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Analysis of Two New Positive Allosteric Modulators of GluA2 Desensitization and Deactivation

Timm¹,

Benveniste²,

Weeks³

et al. 2011

Mol Pharmacol

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At the dimer interface of the extracellular ligand-binding domain of ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors a hydrophilic pocket is formed that is known to interact with two classes of positive allosteric modulators, represented by cyclothiazide and the ampakine 2H,3H,6aH-pyrrolidino(2,1-3Ј,2Ј)1,3-oxazino(6Ј,5Ј-5,4)benzo(e)1,4-dioxan-10-one (CX614). Here, we present structural and functional data on two new positive allosteric modulators of AMPA receptors, phenyl-1,4-bisalkylsulfonamide (CMPDA) and phenyl-1,4-bis-carboxythiophene (CMPDB). Crystallographic data show that these compounds bind within the modulator-binding pocket and that substituents of each compound overlap with distinct moieties of cyclothiazide and CX614. The goals of the present study were to determine 1) the degree of modulation by CMPDA and CMPDB of AMPA receptor deactivation and desensitization; 2) whether these compounds are splice isoform-selective; and 3) whether predictions of mechanism of action could be inferred by comparing molecular interactions between the ligand-binding domain and each compound with those of cyclothiazide and CX614. CMPDB was found to be more isoform-selective than would be predicted from initial binding assays. It is noteworthy that these new compounds are both more potent and more effective and may be more clinically relevant than the AMPA receptor modulators described previously.

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Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits

Cited by 55 publications

References 98 publications

Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters

Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters

Reduced effect of stimulation of AMPA receptors on cerebral O2 consumption in a rat model of autism

Structural and Functional Analysis of Two New Positive Allosteric Modulators of GluA2 Desensitization and Deactivation

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