Publications by authors named "Stuart G Cull-Candy"

35 Publications

Ca -permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease.

J Physiol 2021 Feb 3. Epub 2021 Feb 3.

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.

AMPA receptors are tetrameric glutamate-gated ion channels that mediate a majority of fast excitatory neurotransmission in the brain. They exist as calcium-impermeable (CI-) and calcium-permeable (CP-) subtypes, the latter of which lacks the GluA2 subunit. CP-AMPARs display an array of distinctive biophysical and pharmacological properties that allow them to be functionally identified. This has revealed that they play crucial roles in diverse forms of central synaptic plasticity. Here we summarise the functional hallmarks of CP-AMPARs and describe how these are modified by the presence of auxiliary subunits that have emerged as pivotal regulators of AMPARs. A lasting change in the prevalence of GluA2-containing AMPARs, and hence in the fraction of CP-AMPARs, is a feature in many maladaptive forms of synaptic plasticity and neurological disorders. These include modifications of glutamatergic transmission induced by inflammatory pain, fear conditioning, cocaine exposure, and anoxia-induced damage in neurons and glia. Furthermore, defective RNA editing of GluA2 can cause altered expression of CP-AMPARs and is implicated in motor neuron damage (amyotrophic lateral sclerosis) and the proliferation of cells in malignant gliomas. A number of the players involved in CP-AMPAR regulation have been identified, providing useful insight into interventions that may prevent the aberrant CP-AMPAR expression. Furthermore, recent molecular and pharmacological developments, particularly the discovery of TARP subtype-selective drugs, offer the exciting potential to modify some of the harmful effects of increased CP-AMPAR prevalence in a brain region-specific manner.
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http://dx.doi.org/10.1113/JP279029DOI Listing
February 2021

Homomeric GluA2(R) AMPA receptors can conduct when desensitized.

Nat Commun 2019 09 20;10(1):4312. Epub 2019 Sep 20.

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.

Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors (AMPARs), which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we present evidence that homomeric Q/R-edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (γ-2, γ-8 or GSG1L), generates large fractional steady-state currents and anomalous current-variance relationships. Our results from fluctuation analysis, single-channel recording, and kinetic modeling, suggest that the steady-state current is mediated predominantly by conducting desensitized receptors. When combined with crystallography this unique functional readout of a hitherto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes.
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http://dx.doi.org/10.1038/s41467-019-12280-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754398PMC
September 2019

Altered Cerebellar Short-Term Plasticity but No Change in Postsynaptic AMPA-Type Glutamate Receptors in a Mouse Model of Juvenile Batten Disease.

eNeuro 2018 Mar-Apr;5(2). Epub 2018 May 17.

Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.

Juvenile Batten disease is the most common progressive neurodegenerative disorder of childhood. It is associated with mutations in the gene, causing loss of function of CLN3 protein and degeneration of cerebellar and retinal neurons. It has been proposed that changes in granule cell AMPA-type glutamate receptors (AMPARs) contribute to the cerebellar dysfunction. In this study, we compared AMPAR properties and synaptic transmission in cerebellar granule cells from wild-type and knock-out mice. In cells, the amplitude of AMPA-evoked whole-cell currents was unchanged. Similarly, we found no change in the amplitude, kinetics, or rectification of synaptic currents evoked by individual quanta, or in their underlying single-channel conductance. We found no change in cerebellar expression of GluA2 or GluA4 protein. By contrast, we observed a reduced number of quantal events following mossy-fiber stimulation in Sr, altered short-term plasticity in conditions of reduced extracellular Ca, and reduced mossy fiber vesicle number. Thus, while our results suggest early presynaptic changes in the mouse model of juvenile Batten disease, they reveal no evidence for altered postsynaptic AMPARs.
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http://dx.doi.org/10.1523/ENEURO.0387-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956745PMC
January 2019

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

Cell Rep 2017 08;20(5):1123-1135

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.celrep.2017.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554777PMC
August 2017

TARP γ-2 Is Required for Inflammation-Associated AMPA Receptor Plasticity within Lamina II of the Spinal Cord Dorsal Horn.

J Neurosci 2017 06 30;37(25):6007-6020. Epub 2017 May 30.

Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom

In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking () mice. Examination of EPSCs revealed the targeting of γ-2 to be synapse-specific; the amplitude of spontaneously occurring miniature EPSCs (mEPSCs) was reduced in neurons from mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that γ-2 is associated with AMPARs at synapses in lamina II but excluded from those at C-fiber inputs, a view supported by our immunohistochemical colabeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium-permeable (CP) AMPARs. This effect was abolished in mice. Our results establish that, although γ-2 is not typically associated with calcium-impermeable AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation. In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically determine the functional properties of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. An increase in the excitability of neurons within the superficial dorsal horn (SDH) of the spinal cord is thought to underlie heighted pain sensitivity. One mechanism considered to contribute to such long-lived changes is the remodeling of the ionotropic AMPA-type glutamate receptors that underlie fast excitatory synaptic transmission in the SDH. Here we show that the TARP γ-2 (stargazin) is present in SDH neurons and is necessary in a form of inflammatory pain-induced plasticity, which involves an increase in the prevalence of synaptic calcium-permeable AMPARs.
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http://dx.doi.org/10.1523/JNEUROSCI.0772-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481940PMC
June 2017

Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins.

Neuron 2017 May;94(4):713-730

Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK. Electronic address:

AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. Whereas NMDA receptors gate channels with slow kinetics, responsible primarily for generating long-term synaptic potentiation and depression, AMPARs are the main fast transduction elements at synapses and are critical for the expression of plasticity. The kinetic and conductance properties of AMPARs are laid down during their biogenesis and are regulated by post-transcriptional RNA editing, splice variation, post-translational modification, and subunit composition. Furthermore, AMPAR assembly, trafficking, and functional heterogeneity depends on a large repertoire of auxiliary subunits-a feature that is particularly striking for this type of iGluR. Here, we discuss how the subunit structure, stoichiometry, and auxiliary subunits generate a heterogeneous plethora of receptors, each tailored to fulfill a vital role in fast synaptic signaling and plasticity.
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http://dx.doi.org/10.1016/j.neuron.2017.04.009DOI Listing
May 2017

Auxiliary Subunit GSG1L Acts to Suppress Calcium-Permeable AMPA Receptor Function.

J Neurosci 2015 Dec;35(49):16171-9

Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom

Unlabelled: AMPA-type glutamate receptors are ligand-gated cation channels responsible for a majority of the fast excitatory synaptic transmission in the brain. Their behavior and calcium permeability depends critically on their subunit composition and the identity of associated auxiliary proteins. Calcium-permeable AMPA receptors (CP-AMPARs) contribute to various forms of synaptic plasticity, and their dysfunction underlies a number of serious neurological conditions. For CP-AMPARs, the prototypical transmembrane AMPAR regulatory protein stargazin, which acts as an auxiliary subunit, enhances receptor function by increasing single-channel conductance, slowing channel gating, increasing calcium permeability, and relieving the voltage-dependent block by endogenous intracellular polyamines. We find that, in contrast, GSG1L, a transmembrane auxiliary protein identified recently as being part of the AMPAR proteome, acts to reduce the weighted mean single-channel conductance and calcium permeability of recombinant CP-AMPARs, while increasing polyamine-dependent rectification. To examine the effects of GSG1L on native AMPARs, we manipulated its expression in cerebellar and hippocampal neurons. Transfection of GSG1L into mouse cultured cerebellar stellate cells that lack this protein increased the inward rectification of mEPSCs. Conversely, shRNA-mediated knockdown of endogenous GSG1L in rat cultured hippocampal pyramidal neurons led to an increase in mEPSC amplitude and in the underlying weighted mean single-channel conductance, revealing that GSG1L acts to suppress current flow through native CP-AMPARs. Thus, our data suggest that GSG1L extends the functional repertoire of AMPAR auxiliary subunits, which can act not only to enhance but also diminish current flow through their associated AMPARs.

Significance Statement: Calcium-permeable AMPA receptors (CP-AMPARs) are an important group of receptors for the neurotransmitter glutamate. These receptors contribute to various forms of synaptic plasticity, and alterations in their expression or regulation are also seen in a number of serious neurological conditions, including stroke, motor neuron disease, and cocaine addiction. Several groups of auxiliary transmembrane proteins have been described that enhance the function and cell-surface expression of AMPARs. We now report that the recently identified auxiliary protein GSG1L decreases weighted mean channel conductance and calcium permeability of CP-AMPARs while increasing polyamine-dependent rectification by diminishing outward current. Our experiments reveal that GSG1L is an auxiliary subunit that can markedly suppress CP-AMPAR function, in both recombinant systems and central neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.2152-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682783PMC
December 2015

Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischaemia and acidosis in hippocampal CA1 neurons.

J Physiol 2015 Oct 18;593(19):4373-86. Epub 2015 Aug 18.

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.

Key Points: The hippocampal CA1 region is highly vulnerable to ischaemic stroke. Two forms of AMPA receptor (AMPAR) plasticity - an anoxic form of long-term potentiation and a delayed increase in Ca(2+) -permeable (CP) AMPARs - contribute to this susceptibility by increasing excitotoxicity. In CA1, the acid-sensing ion channel 1a (ASIC1a) is known to facilitate LTP and contribute to ischaemic acidotoxicity. We have examined the role of ASIC1a in AMPAR ischaemic plasticity in organotypic hippocampal slice cultures exposed to oxygen glucose deprivation (a model of ischaemic stroke), and in hippocampal pyramidal neuron cultures exposed to acidosis. We find that ASIC1a activation promotes both forms of AMPAR plasticity and that neuroprotection, by inhibiting ASIC1a, circumvents any further benefit of blocking CP-AMPARs. Our observations establish a new interaction between acidotoxicity and excitotoxicity, and provide insight into the role of ASIC1a and CP-AMPARs in neurodegeneration. Specifically, we propose that ASIC1a activation drives certain post-ischaemic forms of CP-AMPAR plasticity.

Abstract: The CA1 region of the hippocampus is particularly vulnerable to ischaemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischaemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca(2+) -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a), which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischaemic neuronal death and to physiologically induced LTP. This raises the question does ASIC1a activation drive the post-ischaemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPNs) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischaemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischaemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.
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http://dx.doi.org/10.1113/JP270701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594240PMC
October 2015

The First 50 Years of Molecular Pharmacology.

Mol Pharmacol 2015 Jul 5;88(1):139-40. Epub 2015 May 5.

Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California (J.H.B., P.A.I.); Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington (W.A.C.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee (P.J.C.); Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom (S.G.C.-C.); Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (R.D., S.F.T.); Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (T.K.H.); and Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (G.M.)

In this Perspective, former and current editors of Molecular Pharmacology, together with the guest editors for this 50th Anniversary Issue, provide a historical overview of the journal since its founding in 1965. The substantial impact that Molecular Pharmacology has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the journal, Molecular Pharmacology today remains an outstanding venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biologic targets.
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http://dx.doi.org/10.1124/mol.115.099564DOI Listing
July 2015

GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury.

Nat Neurosci 2015 May 30;18(5):674-82. Epub 2015 Mar 30.

Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. NG2-expressing oligodendrocyte precursor cells (NG2 cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2 cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor-mediated synaptic input to NG2 cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2 cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2 cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI.
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http://dx.doi.org/10.1038/nn.3990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459267PMC
May 2015

Transmembrane AMPAR regulatory protein γ-2 is required for the modulation of GABA release by presynaptic AMPARs.

J Neurosci 2015 Mar;35(10):4203-14

Department of Neuroscience Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom

Presynaptic ionotropic glutamate receptors (iGluRs) play important roles in the control of synaptogenesis and neurotransmitter release, yet their regulation is poorly understood. In particular, the contribution of transmembrane auxiliary proteins, which profoundly shape the trafficking and gating of somatodendritic iGluRs, is unknown. Here we examined the influence of transmembrane AMPAR regulatory proteins (TARPs) on presynaptic AMPARs in cerebellar molecular layer interneurons (MLIs). 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a partial agonist at TARP-associated AMPARs, enhanced spontaneous GABA release in wild-type mice but not in stargazer mice that lack the prototypical TARP stargazin (γ-2). These findings were replicated in mechanically dissociated Purkinje cells with functional adherent synaptic boutons, demonstrating the presynaptic locus of modulation. In dissociated Purkinje cells from stargazer mice, AMPA was able to enhance mIPSC frequency, but only in the presence of the positive allosteric modulator cyclothiazide. Thus, ordinarily, presynaptic AMPARs are unable to enhance spontaneous release without γ-2, which is required predominantly for its effects on channel gating. Presynaptic AMPARs are known to reduce action potential-driven GABA release from MLIs. Although a G-protein-dependent non-ionotropic mechanism has been suggested to underlie this inhibition, paradoxically we found that γ-2, and thus AMPAR gating, was required. Following glutamate spillover from climbing fibers or application of CNQX, evoked GABA release was reduced; in stargazer mice such effects were markedly attenuated in acute slices and abolished in the dissociated Purkinje cell-nerve bouton preparation. We suggest that γ-2 association, by increasing charge transfer, allows presynaptic AMPARs to depolarize the bouton membrane sufficiently to modulate both phasic and spontaneous release.
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http://dx.doi.org/10.1523/JNEUROSCI.4075-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355196PMC
March 2015

Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating.

Cell Rep 2014 Oct 16;9(2):728-40. Epub 2014 Oct 16.

Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address:

AMPA-type glutamate receptors (AMPARs) mediate fast neurotransmission at excitatory synapses. The extent and fidelity of postsynaptic depolarization triggered by AMPAR activation are shaped by AMPAR auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). TARPs profoundly influence gating, an effect thought to be mediated by an interaction with the AMPAR ion channel and ligand binding domain (LBD). Here, we show that the distal N-terminal domain (NTD) contributes to TARP modulation. Alterations in the NTD-LBD linker result in TARP-dependent and TARP-selective changes in AMPAR gating. Using peptide arrays, we identify a TARP interaction region on the NTD and define the path of TARP contacts along the LBD surface. Moreover, we map key binding sites on the TARP itself and show that mutation of these residues mediates gating modulation. Our data reveal a TARP-dependent allosteric role for the AMPAR NTD and suggest that TARP binding triggers a drastic reorganization of the AMPAR complex.
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http://dx.doi.org/10.1016/j.celrep.2014.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405707PMC
October 2014

Molecular mechanisms contributing to TARP regulation of channel conductance and polyamine block of calcium-permeable AMPA receptors.

J Neurosci 2014 Aug;34(35):11673-83

Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom

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 γ-2 (stargazin) on GluA1 and GluA4 CP-AMPARs. First, we compared the permeation of organic cations of different sizes. We found that γ-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 γ-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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http://dx.doi.org/10.1523/JNEUROSCI.0383-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145172PMC
August 2014

TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs.

Nat Neurosci 2013 Sep 21;16(9):1266-74. Epub 2013 Jul 21.

Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

Regulation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial in normal synaptic function and neurological disease states. Although transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2) modulate the properties of calcium-impermeable AMPARs (CI-AMPARs) and promote their synaptic targeting, the TARP-specific rules governing CP-AMPAR synaptic trafficking remain unclear. We used RNA interference to manipulate AMPAR-subunit and TARP expression in γ-2-lacking stargazer cerebellar granule cells--the classic model of TARP deficiency. We found that TARP γ-7 selectively enhanced the synaptic expression of CP-AMPARs and suppressed CI-AMPARs, identifying a pivotal role of γ-7 in regulating the prevalence of CP-AMPARs. In the absence of associated TARPs, both CP-AMPARs and CI-AMPARs were able to localize to synapses and mediate transmission, although their properties were altered. Our results also establish that TARPed synaptic receptors in granule cells require both γ-2 and γ-7 and reveal an unexpected basis for the loss of AMPAR-mediated transmission in stargazer mice.
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http://dx.doi.org/10.1038/nn.3473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858651PMC
September 2013

A role of TARPs in the expression and plasticity of calcium-permeable AMPARs: evidence from cerebellar neurons and glia.

Neuropharmacology 2013 Nov 11;74:76-85. Epub 2013 Apr 11.

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

The inclusion of GluA2 subunits has a profound impact on the channel properties of AMPA receptors (AMPARs), in particular rendering them impermeable to calcium. While GluA2-containing AMPARs are the most abundant in the central nervous system, GluA2-lacking calcium-permeable AMPARs are also expressed in wide variety of neurons and glia. Accumulating evidence suggests that the dynamic control of the GluA2 content of AMPARs plays a critical role in development, synaptic plasticity, and diverse neurological conditions ranging from ischemia-induced brain damage to drug addiction. It is thus important to understand the molecular mechanisms involved in regulating the balance of AMPAR subtypes, particularly the role of their co-assembled auxiliary subunits. The discovery of transmembrane AMPAR regulatory proteins (TARPs), initially within the cerebellum, has transformed the field of AMPAR research. It is now clear that these auxiliary subunits play a key role in multiple aspects of AMPAR trafficking and function in the brain. Yet, their precise role in AMPAR subtype-specific regulation has only recently received particular attention. Here we review recent findings on the differential regulation of calcium-permeable (CP-) and -impermeable (CI-) AMPARs in cerebellar neurons and glial cells, and discuss the critical involvement of TARPs in this process. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.
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http://dx.doi.org/10.1016/j.neuropharm.2013.03.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751754PMC
November 2013

TARP-associated AMPA receptors display an increased maximum channel conductance and multiple kinetically distinct open states.

J Physiol 2012 Nov 17;590(22):5723-38. Epub 2012 Sep 17.

Department of Neuroscience, University College London, Gower Street, London WC1E 6BT, UK.

Fast excitatory synaptic transmission in the CNS is mediated mainly by AMPA-type glutamate receptors (AMPARs), whose biophysical properties are dramatically modulated by the presence of transmembrane AMPAR regulatory proteins (TARPs). To help construct a kinetic model that will realistically describe native AMPAR/TARP function, we have examined the single-channel properties of homomeric GluA1 AMPARs in combination with the TARPs, γ-2, γ-4 and γ-5. In a saturating concentration of agonist, each of these AMPAR/TARP combinations gave rise to single-channel currents with multiple conductance levels that appeared intrinsic to the receptor-channel complex, and showed long-lived subconductance states. The open time and burst length distributions of the receptor complexes displayed multiple dwell-time components. In the case of γ-2- and γ-4-associated receptors, these distributions included a long-lived component lasting tens of milliseconds that was absent from both GluA1 alone and γ-5-associated receptors. The open time distributions for each conductance level required two dwell-time components, indicating that at each conductance level the channel occupies a minimum of two kinetically distinct open states. We have explored how these data place novel constraints on possible kinetic models of TARP-associated AMPARs that may be used to define AMPAR-mediated synaptic transmission.
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http://dx.doi.org/10.1113/jphysiol.2012.238006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528987PMC
November 2012

Cornichons modify channel properties of recombinant and glial AMPA receptors.

J Neurosci 2012 Jul;32(29):9796-804

Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.

Ionotropic glutamate receptors, which underlie a majority of excitatory synaptic transmission in the CNS, associate with transmembrane proteins that modify their intracellular trafficking and channel gating. Significant advances have been made in our understanding of AMPA-type glutamate receptor (AMPAR) regulation by transmembrane AMPAR regulatory proteins. Less is known about the functional influence of cornichons-unrelated AMPAR-interacting proteins, identified by proteomic analysis. Here we confirm that cornichon homologs 2 and 3 (CNIH-2 and CNIH-3), but not CNIH-1, slow the deactivation and desensitization of both GluA2-containing calcium-impermeable and GluA2-lacking calcium-permeable (CP) AMPARs expressed in tsA201 cells. CNIH-2 and -3 also enhanced the glutamate sensitivity, single-channel conductance, and calcium permeability of CP-AMPARs while decreasing their block by intracellular polyamines. We examined the potential effects of CNIHs on native AMPARs by recording from rat optic nerve oligodendrocyte precursor cells (OPCs), known to express a significant population of CP-AMPARs. These glial cells exhibited surface labeling with an anti-CNIH-2/3 antibody. Two features of their AMPAR-mediated currents-the relative efficacy of the partial agonist kainate (I(KA)/I(Glu) ratio 0.4) and a greater than fivefold potentiation of kainate responses by cyclothiazide-suggest AMPAR association with CNIHs. Additionally, overexpression of CNIH-3 in OPCs markedly slowed AMPAR desensitization. Together, our experiments support the view that CNIHs are capable of altering key properties of AMPARs and suggest that they may do so in glia.
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http://dx.doi.org/10.1523/JNEUROSCI.0345-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428874PMC
July 2012

Channel properties reveal differential expression of TARPed and TARPless AMPARs in stargazer neurons.

Nat Neurosci 2012 Jun;15(6):853-61

Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

Dynamic regulation of calcium-permeable AMPA receptors (CP-AMPARs) is important for normal synaptic transmission, plasticity and pathological changes. Although the involvement of transmembrane AMPAR regulatory proteins (TARPs) in trafficking of calcium-impermeable AMPARs (CI-AMPARs) has been extensively studied, their role in the surface expression and function of CP-AMPARs remains unclear. We examined AMPAR-mediated currents in cerebellar stellate cells from stargazer mice, which lack the prototypical TARP stargazin (g-2). We found a marked increase in the contribution of CP-AMPARs to synaptic responses, indicating that, unlike CI-AMPARs, these can localize at synapses in the absence of g-2. In contrast with CP-AMPARs in extrasynaptic regions, synaptic CP-AMPARs displayed an unexpectedly low channel conductance and strong block by intracellular spermine, suggesting that they were ‘TARPless’. As a proof of principle that TARP association is not an absolute requirement for AMPAR clustering at synapses, miniature excitatory postsynaptic currents mediated by TARPless AMPARs were readily detected in stargazer granule cells following knockdown of their only other TARP, g-7.
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http://dx.doi.org/10.1038/nn.3107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427011PMC
June 2012

Bidirectional plasticity of calcium-permeable AMPA receptors in oligodendrocyte lineage cells.

Nat Neurosci 2011 Oct 9;14(11):1430-8. Epub 2011 Oct 9.

Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

Oligodendrocyte precursor cells (OPCs), a major glial cell type that gives rise to myelinating oligodendrocytes in the CNS, express calcium-permeable AMPA receptors (CP-AMPARs). Although CP-AMPARs are important for OPC proliferation and neuron-glia signaling, they render OPCs susceptible to ischemic damage in early development. We identified factors controlling the dynamic regulation of AMPAR subtypes in OPCs from rat optic nerve and mouse cerebellar cortex. We found that activation of group 1 mGluRs drove an increase in the proportion of CP-AMPARs, reflected by an increase in single-channel conductance and inward rectification. This plasticity required the elevation of intracellular calcium and used PI3K, PICK-1 and the JNK pathway. In white matter, neurons and astrocytes release both ATP and glutamate. Unexpectedly, activation of purinergic receptors in OPCs decreased CP-AMPAR expression, suggesting a capacity for homeostatic regulation. Finally, we found that stargazin-related transmembrane AMPAR regulatory proteins, which are critical for AMPAR surface expression in neurons, regulate CP-AMPAR plasticity in OPCs.
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http://dx.doi.org/10.1038/nn.2942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204222PMC
October 2011

Probing TARP modulation of AMPA receptor conductance with polyamine toxins.

J Neurosci 2011 May;31(20):7511-20

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA.

The properties of synaptic AMPA receptors (AMPARs) depend on their subunit composition and association with transmembrane AMPAR regulatory proteins (TARPs). Although both GluA2 incorporation and TARP association have been shown to influence AMPAR channel conductance, the manner in which different TARPs modulate the mean channel conductance of GluA2-containing AMPARs is unknown. Using ultrafast agonist application and nonstationary fluctuation analysis, we found that TARP subtypes differentially increase the mean channel conductance, but not the peak open probability, of recombinant GluA2-containing AMPARs. TARP γ-8, in particular, enhances mean channel conductance to a greater degree than γ-2, γ-3, or γ-4. We then examined the action of a use-dependent antagonist of GluA2-containing AMPARs, philanthotoxin-74 (PhTx-74), on recombinant AMPARs and on GluA2-containing AMPARs in cerebellar granule neurons from stargazer mice transfected with TARPs. We found that the rate and extent of channel block varies with TARP subtype, in a manner that correlates linearly with mean channel conductance. Furthermore, block of GluA2-containing AMPARs by polyamine toxins varied depending on whether channels were activated by the full agonist glutamate or the partial agonist kainate, consistent with conductance state-dependent block. Block of GluA2-lacking AMPARs by PhTx-433 is also modulated by TARP association and is a function of agonist efficacy. Our data indicate that channel block by polyamine toxins is sensitive to the mean channel conductance of AMPARs, which varies with TARP subtype and agonist efficacy. Furthermore, our results illustrate the utility of polyamine toxins as sensitive probes of AMPAR channel conductance and suggest the possibility that TARPs may influence their channel properties by selectively stabilizing specific channel conformations, rather than altering the pore structure.
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http://dx.doi.org/10.1523/JNEUROSCI.6688-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164836PMC
May 2011

Lithium acts as a potentiator of AMPAR currents in hippocampal CA1 cells by selectively increasing channel open probability.

J Physiol 2010 Oct 31;588(Pt 20):3933-41. Epub 2010 Aug 31.

Institute for Neurophysiology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Recent evidence suggests that lithium, which is used in the treatment of bipolar disorders, may act by influencing AMPAR properties at central glutamatergic synapses. While it is clear that lithium potentiates recombinant AMPAR responses in a subunit specific way, the origin of this potentiation is not known. We examined the effects of lithium on native AMPAR channels in CA1 pyramidal cells in hippocampal slices where AMPARs are expected to be associated with auxiliary subunits. We found that lithium produced a selective increase in single-channel open probability (P(open)), with little effect on single-channel conductance or burst length. From the present and previous finding it is likely that lithium causes a reduction in the time to recovery from desensitization, resulting in the observed increase in P(open). This would be consistent with the view that lithium acts like certain other allosteric AMPAR modulators to reduce the time spent in the desensitized state, but differs from those that act by slowing dissociation of glutamate.
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http://dx.doi.org/10.1113/jphysiol.2010.195115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000583PMC
October 2010

Desensitization and models of receptor-channel activation.

J Physiol 2010 May;588(Pt 9):1395-7

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

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http://dx.doi.org/10.1113/jphysiol.2010.188664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876797PMC
May 2010

Neuroscience. AMPA receptors--another twist?

Science 2010 Mar;327(5972):1463-5

Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

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http://dx.doi.org/10.1126/science.1187920DOI Listing
March 2010

Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors.

Nat Neurosci 2009 May 19;12(5):593-601. Epub 2009 Apr 19.

Department of Neuroscience, Physiology and Pharmacology, University College London, UK.

In contrast with conventional NMDA receptor-dependent synaptic plasticity, the synaptic events controlling the plasticity of GluR2-lacking Ca(2+)-permeable AMPA receptors (CP-AMPARs) remain unclear. At parallel fiber synapses onto cerebellar stellate cells, Ca(2+) influx through AMPARs triggers a switch in AMPAR subunit composition, resulting in loss of Ca(2+) permeabilty. Paradoxically, synaptically induced depolarization will suppress this Ca(2+) entry by promoting polyamine block of CP-AMPARs. We therefore examined other mechanisms that may control this receptor regulation under physiological conditions. We found that activation of both mGluRs and CP-AMPARs is necessary and sufficient to drive an AMPAR subunit switch and that by enhancing mGluR activity, GABA(B)R activation promotes this plasticity. Furthermore, we found that mGluRs and GABA(B)Rs are tonically activated, thus setting the basal tone for EPSC amplitude and rectification. Regulation by both excitatory and inhibitory inputs provides an unexpected mechanism that determines the potential of these synapses to show dynamic changes in AMPAR Ca(2+) permeability.
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http://dx.doi.org/10.1038/nn.2309DOI Listing
May 2009

Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, gamma-5.

Nat Neurosci 2009 Mar 22;12(3):277-85. Epub 2009 Feb 22.

Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

Although the properties and trafficking of AMPA-type glutamate receptors (AMPARs) depend critically on associated transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (gamma-2), no TARP has been described that can specifically regulate the important class of calcium-permeable (CP-) AMPARs. We examined the stargazin-related protein gamma-5, which is highly expressed in Bergmann glia, a cell type possessing only CP-AMPARs. gamma-5 was previously thought not to be a TARP, and it has been widely used as a negative control. Here we find that, contrary to expectation, gamma-5 acts as a TARP and serves this role in Bergmann glia. Whereas gamma-5 interacts with all AMPAR subunits, and modifies their behavior to varying extents, its main effect is to regulate the function of AMPAR subunit combinations that lack short-form subunits, which constitute predominantly CP-AMPARs. Our results suggest an important role for gamma-5 in regulating the functional contribution of CP-AMPARs.
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http://dx.doi.org/10.1038/nn.2266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735763PMC
March 2009

Climbing-fibre activation of NMDA receptors in Purkinje cells of adult mice.

J Physiol 2007 Nov 27;585(Pt 1):91-101. Epub 2007 Sep 27.

Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

Among principal neurons, adult Purkinje cells have long been considered unusual in lacking functional NMDA receptors. This view has emerged largely from studies on rats, where NMDA receptors are expressed in Purkinje cells of newborn animals, but are lost after 2 weeks. By contrast, immunolabelling data have shown that Purkinje cells from adult mice express multiple NMDA receptor subunits, suggesting a possible species difference. To investigate the presence of functional NMDA receptors in Purkinje cells of mice, and to explore the contribution of different receptor subunits, we made whole-cell and single-channel patch-clamp recordings from Purkinje cells of wild-type and NR2D-/- mice of different ages. Here we report that multiple NMDA receptor subtypes are indeed expressed in Purkinje cells of young and adult mice; in the adult, both NR2A- and NR2B-containing subtypes are present. Furthermore, we show that NMDA receptor-mediated EPSCs can be evoked by climbing fibre stimulation, and appear to be mediated mainly by NR2A-containing receptors.
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http://dx.doi.org/10.1113/jphysiol.2007.141531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2327252PMC
November 2007

Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors.

Nat Neurosci 2007 Oct 16;10(10):1260-7. Epub 2007 Sep 16.

Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

Endogenous polyamines profoundly affect the activity of various ion channels, including that of calcium-permeable AMPA-type glutamate receptors (CP-AMPARs). Here we show that stargazin, a transmembrane AMPAR regulatory protein (TARP) known to influence transport, gating and desensitization of AMPARs, greatly reduces block of CP-AMPARs by intracellular polyamines. By decreasing CP-AMPAR affinity for cytoplasmic polyamines, stargazin enhances the charge transfer following single glutamate applications and eliminates the frequency-dependent facilitation seen with repeated applications. In cerebellar stellate cells, which express both synaptic CP-AMPARs and stargazin, we found that the rectification and unitary conductance of channels underlying excitatory postsynaptic currents were matched by those of recombinant AMPARs only when the latter were associated with stargazin. Taken together, our observations establish modulatory actions of stargazin that are specific to CP-AMPARs, and suggest that during synaptic transmission the activity of such receptors, and thus calcium influx, is fundamentally changed by TARPs.
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http://dx.doi.org/10.1038/nn1966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430330PMC
October 2007

Influence of agonist concentration on AMPA and kainate channels in CA1 pyramidal cells in rat hippocampal slices.

J Physiol 2006 Jun 9;573(Pt 2):371-94. Epub 2006 Mar 9.

Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

We have determined the functional properties of single AMPA receptor (AMPAR) and kainate receptor channels present in CA1 cells in hippocampal slices, to shed light on the relationship between single-channel behaviour and synaptic currents in these cells. To derive basic properties of AMPA and kainate channels activated by their excitatory transmitter, we examined outside-out patches exposed to glutamate. The kainate agonist SYM 2081, was used to confirm the presence of kainate receptors. Channels activated by glutamate or SYM 2081 exhibited conductance levels of 2-20 pS. Properties of single channels depended on the glutamate or AMPA concentration used. We observed a marked increase in mean channel conductance (gamma) from gamma = 6.9, to 11.2 pS, when glutamate was increased from 10 mum to 10 mm. The kinetic behaviour of AMPAR channels was also influenced by agonist concentration, with an increase in 'bursty' events at higher concentrations. In contrast, kainate channels were characterized by brief openings without bursts. Consistent with the view that 'bursty' events arose from AMPARs, these openings decreased in the presence of the AMPAR blocker GYKI 53655. Furthermore, our experiments revealed a concentration-dependent increase in the number of conductance states during an individual AMPAR opening; AMPAR channels displayed up to four distinct levels. Our results are consistent with the view that the AMPAR channel conductance depends on the number of transmitter molecules bound in CA1 cells. We consider the implications of these findings for the change in EPSC properties during long-term potentiation (LTP).
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http://dx.doi.org/10.1113/jphysiol.2005.102723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779714PMC
June 2006

Changes in synaptic structure underlie the developmental speeding of AMPA receptor-mediated EPSCs.

Nat Neurosci 2005 Oct 18;8(10):1310-8. Epub 2005 Sep 18.

[1] Department of Pharmacology, University College London, UK.

At many excitatory and inhibitory synapses throughout the nervous system, postsynaptic currents become faster as the synapse matures, primarily owing to changes in receptor subunit composition. The origin of the developmental acceleration of AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) remains elusive. We used patch-clamp recordings, electron microscopic immunogold localization of AMPARs, partial three-dimensional reconstruction of the neuropil and numerical simulations of glutamate diffusion and AMPAR activation to examine the factors underlying the developmental speeding of miniature EPSCs in mouse cerebellar granule cells. We found that the main developmental change that permits submillisecond transmission at mature synapses is an alteration in the glutamate concentration waveform as experienced by AMPARs. This can be accounted for by changes in the synaptic structure and surrounding neuropil, rather than by a change in AMPAR properties. Our findings raise the possibility that structural alterations could be a general mechanism underlying the change in the time course of AMPAR-mediated synaptic transmission.
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http://dx.doi.org/10.1038/nn1534DOI Listing
October 2005

Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses.

Nat Neurosci 2005 Jun 15;8(6):768-75. Epub 2005 May 15.

Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

At many excitatory central synapses, activity produces a lasting change in the synaptic response by modifying postsynaptic AMPA receptors (AMPARs). Although much is known about proteins involved in the trafficking of Ca2+-impermeable (GluR2-containing) AMPARs, little is known about protein partners that regulate subunit trafficking and plasticity of Ca2+-permeable (GluR2-lacking) AMPARs. At cerebellar parallel fiber-stellate cell synapses, activity triggers a novel type of plasticity: Ca2+ influx through GluR2-lacking synaptic AMPARs drives incorporation of GluR2-containing AMPARs, generating rapid, lasting changes in excitatory postsynaptic current properties. Here we examine how glutamate receptor interacting protein (GRIP, also known as AMPAR binding protein or ABP) and protein interacting with C-kinase-1 (PICK) regulate subunit trafficking and plasticity. We find that repetitive synaptic activity triggers loss of synaptic GluR2-lacking AMPARs by selectively disrupting their interaction with GRIP and that PICK drives activity-dependent delivery of GluR2-containing receptors. This dynamic regulation of AMPARs provides a feedback mechanism for controlling Ca2+ permeability of synaptic receptors.
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http://dx.doi.org/10.1038/nn1468DOI Listing
June 2005