Review AMPA receptors in the synapse: Very little space and even less time, 2021, Baranovic

[SNT Gatchaman]

AMPA receptors in the synapse: Very little space and even less time
Jelena Baranovic

Glutamate is by far the most abundant neurotransmitter used by excitatory synapses in the vertebrate central nervous system. Once released into the synaptic cleft, it depolarises the postsynaptic membrane and activates downstream signalling pathways resulting in the propagation of the excitatory signal. Initial depolarisation is primarily mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. These ion channels are the first ones to be activated by released glutamate and their kinetics, dynamics and abundance on the postsynaptic membrane defines the strength of the postsynaptic response.

This review focuses on native AMPA receptors and synaptic environment they inhabit and considers structural and functional properties of the receptors obtained in heterologous systems in the light of spatial and temporal constraints of the synapse.

HIGHLIGHTS
• Native AMPA receptors are a part of large complexes residing in the postsynapse.

• Their extracellular domains extend almost half-way across the synaptic cleft.

• They engage in many interactions with transmembrane and secreted synaptic proteins.

• AMPA receptors respond to released glutamate within 1 ms due to its rapid clearance.

• Crowdedness and ms timescale might affect conformations of native AMPA receptors.

Web | Neuropharmacology | Paywall

 

[SNT Gatchaman]

This is a review article on AMPA receptors, whose dysfunction may be implicated by DecodeME findings, and some recent (early) PET/MR studies in LC.

From the bio, the author looks to be an early-career post-doc who leads a dedicated lab (coincidentally, close to DecodeME at the University of Edinburgh).

 

[SNT Gatchaman]

Key quotes (abbreviated) —

Sitting in the postsynaptic membrane, AMPA receptors function as synaptic glutamate sensors – they are the first proteins to be activated by presynaptically released glutamate and activation of their ion channel links presynaptic glutamate release to postsynaptic membrane depolarisation.

AMPA receptors are tetrameric ion channels composed of various combinations of subunits A1-A4. Each subunit has the same modular architecture with amino-terminal and ligand-binding domains forming the extracellular layer (ATDs and LBDs, respectively), followed by the transmembrane region (TM) and intracellular C-terminus.

most native AMPA receptors are di-heteromers […] Surprisingly, a recent cryo-electron microscopy (cryo-EM) study of native (synaptic and extrasynaptic) AMPA receptors purified from rats’ brains revealed, for the first time, that about a third of native AMPA receptors are tri-heteromers […] their functional characteristics as well as their representation in the synapses are currently unknown. In other words, after decades of research, functional properties of many native AMPA receptors remain unknown.

(And diseases associated with their dysfunction might be similarly unknown.)

the functional properties of native AMPA receptors are not only defined by their subunit composition. In fact, AMPA receptors in the synapse are at all times complexed by various other proteins which modulate their trafficking and activity and are hence termed auxiliary subunits. […] three main auxiliary proteins that associate primarily with the transmembrane domain of an AMPA receptor tetramer: Transmembrane AMPA receptor Regulatory Proteins or TARPs (γ2-4, γ7-8), cornichons or CNIHs (2 and 3) and Cystine-Knot AMPA receptor Modulating Protein or CKAMPs

In addition to auxiliary proteins, there are 21 various mostly transmembrane, but also secreted and cytoplasmic proteins loosely associated with AMPA receptor complexes […] The expression of AMPA receptor core subunits as well as auxiliary proteins, varies throughout the adult brain, during development and possibly during synaptic activity, creating a mind-boggling diversity (and perhaps redundancy) of native AMPA receptor complexes […] native AMPA receptors are, in all likelihood, complexed by at least 4 auxiliary subunits at all times.

Apart from directly modulating the function and affecting the structure (see below) of AMPA receptors, the presence of auxiliary proteins, in particular CNIH2 and 3 seems to recruit as yet unidentified lipids into the AMPA receptor complexes […] raises the possibility that membrane lipids might modulate activity, assembly and/or trafficking of native AMPA receptor complexes

Auxiliary proteins not only modulate functional properties of AMPA receptors, but also define their localisation within the synapse by anchoring them to scaffold proteins forming the postsynaptic density

neuroligin-neurexin complex (NL/Nrx) crosses the synaptic cleft by interacting with the PDZ domain of PSD95 on the postsynaptic side via neuroligin and with the PDZ domain of active zone protein CASK on the presynaptic side via neurexin […] One of the consequences of these t synaptic interactions is precise alignment of AMPA receptors with the presynaptic glutamate release sites

Kainate receptors, which are close relatives of AMPA receptors, cluster at postsynaptic sites by binding their ATDs to presynaptically secreted C1ql2 and 3, which in turn also bind neurexin 3 on the presynaptic membrane

 

[SNT Gatchaman]

Key quotes (cont'd) —

while picturing AMPA receptors in the synaptic cleft, one should be reminded that in addition to engaging in pre- and postsynaptic interactions, extracellular domains of AMPA receptors are also immersed in a dense mesh of proteins building the extracellular matrix (ECM). ECM is composed of proteins such as […], laminins, integrins and others and rather than being just a structural scaffold, it also plays an active role in regulation of synaptic plasticity and homeostasis.

A dense network of protein interactions involving AMPA receptors takes place within the confines of a synapse. […] AMPA receptors are carefully organised amidst this network of post- and presynaptic interactions. […] Mathematical modelling indicates that such clustering and precise positioning of AMPA receptors below the presynaptic sites of glutamate release is essential for effective synaptic transmission due to the steep concentration gradient of glutamate in the synaptic cleft

While sitting in such a crowded environment, the role of AMPA receptors is to detect the presence of glutamate in the synaptic cleft, as quickly and as often as possible, in order to reliably report on glutamate release from the presynaptic neuron. In some extreme examples, such as auditory neurons, signal transmission happens in the kilohertz range

(tinnitus)

When one synaptic vesicle fuses with the presynaptic neuron, it releases several thousand (~3500–8000) glutamate molecules into the synaptic cleft […] But AMPA receptors only have about a millisecond to register released glutamate, as it rapidly gets cleared away by diffusion and uptake by glutamate transporters

Synaptic AMPA receptors, thus, work on a millisecond timescale: they activate within 200–600 μs, followed by deactivation within ~3 ms or desensitization within ~10 ms. Upon desensitization, it is suggested the receptors are removed from the synapse within tens of milliseconds through surface diffusion

The extent of conformational change of the desensitized AMPA receptor extracellular layer does have a physiological significance, as these changes have been suggested as a trigger for trafficking of desensitized AMPA receptors out of the synapse

 

[V.R.T.]

Should somebody reach out to this researcher? Seems like an ideal candidate to get interested in MECFS...

 

[SNT Gatchaman]

I thought I should drop her an email.

Edit: sent.