Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond
Introduction
Three main families of mammalian glutamate-gated ion channels have been identified: AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid), kainate- and NMDA (N-methyl-d-aspartate)-receptors. Of these, AMPARs mediate the majority of fast excitatory transmission in the central nervous system (CNS). The subunits forming AMPARs (GluR1–4 or GluRA–D; encoded by genes GRIA1-4) assemble as homo- or heterotetramers, the functional properties of which are dictated by their subunit composition and by the presence of non-pore-forming, auxiliary transmembrane AMPAR-regulatory proteins (TARPs). The mRNAs encoding each subunit type are also subject to post-transcriptional modification, in the form of alternative splicing and RNA editing, contributing further diversity to key aspects of AMPAR behaviour.
One of the most striking of the RNA editing changes affects the GluR2 subunit, resulting in a glutamine (Q) to arginine (R) switch at the ‘Q/R site’ in the pore-lining (M2) region. Editing at this site is nearly 100% efficient, profoundly altering the properties of GluR2-containing AMPARs, rendering them Ca2+-impermeable. This makes the GluR2 subunit a key determinant of AMPAR function. AMPARs that lack the GluR2 subunit are permeable to Ca2+ ions, exhibit a high single-channel conductance, and are blocked in a voltage-dependent manner by endogenous polyamines (giving rise to an inwardly rectifying current-voltage [I/V] relationship).
Although the majority of AMPARs in the CNS are GluR2-containing, and hence Ca2+-impermeable, significant expression of Ca2+-permeable AMPARs is seen in neuronal and glial cells of various brain regions. It is now becoming apparent that the regulation of these Ca2+ permeable AMPARs — their expression, assembly, trafficking and turnover — is crucial in synaptic plasticity, neuronal development and neurological disease. Here, we highlight the emerging significance of Ca2+-permeable AMPARs and consider their importance in relation to normal synaptic function, plasticity, and disease states.
Section snippets
GluR2 controls AMPAR assembly
Assembly of AMPAR tetramers proceeds as a two-step process within the endoplasmic reticulum (ER). This process involves the preferential formation of heterodimers, mediated by the luminal N-termini of the subunits [1, 2, 3], followed by the assembly of a pair of dimers [2]. The presence of a charged arginine residue at the Q/R site of GluR2 strongly influences subunit interactions during tetramerization, such that the juxtaposition of GluR2 subunits of different dimers is energetically
Ca2+ permeable AMPARs and synaptic plasticity
Until recently, our view of synaptic plasticity was based largely on studies of synapses that express mainly Ca2+-impermeable AMPARs. In the hippocampus, for example, basal AMPAR levels are maintained by constitutive AMPAR recycling involving an interaction between GluR2 and the membrane fusion protein NSF [16, 18], whereas receptor internalisation during long-term depression (LTD) is regulated by GluR2 interaction with the clathrin adaptor protein AP2 [14]. By contrast, activity-dependent
PICK, GRIP and NSF mediate changes in Ca2+-permeability
Recent studies [36••, 37••] have investigated the protein partners involved in delivery and anchoring of receptors underlying the activity-dependent plasticity of Ca2+-permeable AMPARs. When peptides that block AMPAR binding to PICK1 or NSF [16, 19] are included in the patch-pipette, there is little effect on cerebellar stellate cell miniature EPSCs (mEPSCs), whereas additionally inhibiting GRIP produces a clear rundown in amplitude [37••]. This reduction occurs only at negative potentials,
Endogenous polyamines dynamically modulate EPSCs
Intracellular polyamines confer a voltage-dependent block on Ca2+-permeable AMPARs. Initial evidence for the involvement of polyamines in synaptic plasticity came from the demonstration that tonic polyamine block of Ca2+-permeable AMPARs is transiently relieved by repetitive stimulation [40, 41] (Figure 2a). This phenomenon reduces paired-pulse depression, resulting in facilitation of synaptic responses that would normally show depression. The degree of facilitation produced depends on the
GluR2 and dendritic spines
Throughout the CNS, neurons that lack spines tend to express Ca2+-permeable AMPARs, raising the possibility that GluR2-lacking AMPARs mediate a form of Ca2+ signalling that does not require the spatial segregation normally afforded by spines. Indeed, in primary visual and somatosensory neocortex, activation of single synapses onto aspiny dendrites of fast-spiking interneurons generates Ca2+ signals that are highly restricted [48]. This ‘spine-free’ mechanism for localizing Ca2+ ‘microdomains’
Regulation of Ca2+-permeable AMPARs in disease
The dynamic properties of Ca2+-permeable AMPARs, evident in different forms of plasticity, are also relevant to various neurological conditions. Changes in the expression Ca2+-permeable AMPARs can alter synaptic properties, Ca2+-dependent signalling cascades, or lead to damage of selectively vulnerable neurons and glial cells [57, 58].
Conclusions and outlook
Far from being a relative rarity, Ca2+-permeable AMPARs are more widespread than originally thought. They are expressed in both neurons and glia, and are activated during synaptic transmission. Even though Ca2+ influx through AMPARs is modest in comparison to that through NMDARs, the location and kinetics of this influx enables it to serve distinct cellular functions. Ca2+ permeable AMPARs are exquisitely regulated in a dynamic manner through changes in subunit expression, editing and polyamine
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We are grateful to the Wellcome Trust for support, and to our colleagues for helpful discussions that have contributed to this article. SG Cull-Candy holds a Royal Society-Wolfson Research Award.
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