Postsynaptic Membranes at the Neuromuscular Junction: Molecular Organisation

Jean Cartaud, CNRS & Université Paris‐Diderot, Paris, France
Ekaterini Kordeli, INSERM & Institut National de la Transfusion Sanguine, Paris, France
Annie Cartaud, CNRS & Université Paris‐Diderot, Paris, France

Published online: April 2010

DOI: 10.1002/9780470015902.a0000252.pub2

Accurate neurotransmission between motor nerve and muscle fibres at the vertebrate cholinergic neuromuscular junction (NMJ) depends on the differentiation of highly specialised structures both pre- and postsynaptically. The accumulation of nicotinic acetylcholine receptors (AChRs) and voltage-gated sodium channels represents the hallmark of postsynaptic membrane differentiation. Several synaptic organising proteins are required for the aggregation of postsynaptic AChRs. The muscle-specific receptor tyrosine kinase (MuSK) provides a structural scaffold necessary to initiate aggregates of postsynaptic molecules. Agrin – a nerve-derived extracellular matrix glycoprotein – is required for AChR clustering probably by activating MuSK activity. Rapsyn – the AChR-associated peripheral protein acting downstream of agrin–MuSK signalling – is essential for AChR clustering. These proteins, together with a wealth of other components of the synapse, cooperate in multiple ways to play both structural and signalling roles in synaptic differentiation. Synaptopathies of the NMJ result from mutations in several key players of synaptic differentiation.

Key Concepts:

  • Efficient communication between neurons or between neurons and their targets requires the enrichment of synaptic proteins, in particular, ligand-gated ion channels at postsynaptic sites.
  • The NMJ represents a particularly striking example of accumulation of nicotinic acetylcholine receptors in the postsynaptic membrane and is an ideal model to study receptor clustering.
  • Formation and maintenance of the postsynaptic membrane is a complex mechanism involving synaptic organising molecules derived both from nerve and muscle.
  • The muscle tyrosine kinase, MuSK, is the master organiser of the NMJ capable to initiate clustering of postsynaptic components, even in the absence of neuronal cues.
  • Mutations in several components of the postsynaptic membrane (not only in AChR subunits genes but also in agrin, ColQ, DOK-7, laminin, MuSK, rapsyn, etc.) result in severe dysfunction of the NMJ: the congenital myasthenic syndromes.

Keywords: acetylcholinesterase; agrin; congenital myasthenic syndromes; nicotinic acetylcholine receptor; voltage-sensitive sodium channel; rapsyn; synapse

Figure 1. Electron micrographs of the postsynaptic apparatus of the mouse NMJ. The postsynaptic membrane just beneath the nerve ending (NE) is folded up into numerous folds. Note the electron-dense appearance of the membrane at the top of the folds where AChRs are concentrated (arrows in (b)). Magnifications: (a) ×20 000, (b) ×38 000. Inset: Double fluorescence image showing the localisation of AChRs (labelled with fluorescein-conjugated -bungarotoxin, green fluorescence) and ankyrin-G (red fluorescence), at the top and at the base of the folds, respectively. Magnification ×1600.
Figure 2. (a) Electron micrograph showing the densely packed AChR rosettes in purified AChR-rich membrane from Torpedo electric tissue (negative staining; magnification ×300 000). Inset: Detail of an AChR molecule exhibiting a pentameric structure; magnification ×600 000. (b) Electron micrograph of a freeze-etched AChR-rich postsynaptic membrane fragment showing the quasi-geometrical arrangement of the AChRs in the plane of the membrane (magnification ×200 000).
Figure 3. Electron micrographs of negatively stained AChE molecules. The asymmetric form A12 (inset) aggregates at low ionic strength and in the presence of polyanions into discrete assemblies containing up to six molecules organised head to tail at both ends of a bundle of collagenic subunits. Similar aggregates are likely to occur in situ in the basal lamina. Arrows point to the collagenic tail in the isolated A12 molecule in the inset and in one aggregate. Magnification ×300 000.
Figure 4. Model of the molecular specialisation of the postsynaptic membrane and of the basal lamina at the vertebrate NMJ. Distinct sets of molecules are segregated in the crests (a) and the troughs (b) of the postjunctional folds. The representation of the molecular organisation of the membrane and extracellular matrix is oversimplified to highlight the interactions between the major structural and functional components in both domains. Molecules are not drawn at scale and the stoichiometry between the various elements is roughly indicated. ECM, extracellular matrix and PM, postsynaptic membrane.
Figure 5. Schematic representation of the signalling pathways leading to AChR clustering and stabilisation. Agrin released from nerve terminal activates the Lrp4/MuSK complex that in turn activates multiple signalling pathways leading to AChR clustering through remodelling of the actin cytoskeleton. Tid1 operates downstream of MuSK by incorporating Dok-7 in the complex in an agrin-dependant manner. Tid1 may trigger reorganisation of the postsynaptic cytoskeleton by interacting with APC, and by activating small Rho GTPases through Dvl and PAK1 localised at synaptic sites via activation of MuSK. Rapsyn is also believed to be required for agrin-induced AChR clustering and stabilisation via Src-like kinase presentation to the AChR. Wnt signalling has recently been implicated in the formation of the NMJ. Acetylcholine may disperse AChR clusters possibly by a mechanism involving Cdk5. Stars represent tyrosine phosphorylation of MuSK and AChRs. Adapted from Song and Balice-Gordon (2008).
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Related Sub-Topics:

Ion Channels | Receptors for Neurotransmitters | Synaptic Transmission | Postsynaptic Signalling Mechanisms | Membrane Proteins
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Article Title: Postsynaptic Membranes at the Neuromuscular Junction: Molecular Organisation
 
How to Cite close
Cartaud, Jean, Kordeli, Ekaterini, and Cartaud, Annie(Apr 2010) Postsynaptic Membranes at the Neuromuscular Junction: Molecular Organisation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000252.pub2]