Clustering of Nicotinic Acetylcholine Receptors: From the Neuromuscular Junction to Interneuronal Synapses

Abstract

Fast and accurate synaptic transmission requires high-density accumulation of neurotransmitter receptors in the postsynaptic membrane. During development of the neuromuscular junction, clustering of acetylcholine receptors (AChR) is one of the first signs of postsynaptic specialization and is induced by nerve-released agrin. Recent studies have revealed that different mechanisms regulate assembly vs stabilization of AChR clusters and of the postsynaptic apparatus. MuSK, a receptor tyrosine kinase and component of the agrin receptor, and rapsyn, an AChR-associated anchoring protein, play crucial roles in the postsynaptic assembly. Once formed, AChR clusters and the postsynaptic membrane are stabilized by components of the dystrophin/utrophin glycoprotein complex, some of which also direct aspects of synaptic maturation such as formation of postjunctional folds. Nicotinic receptors are also expressed across the peripheral and central nervous system (PNS/CNS). These receptors are localized not only at the pre-but also at the postsynaptic sites where they carry out major synaptic transmission. In neurons, they are found as clusters at synaptic or extrasynaptic sites, suggesting that different mechanisms might underlie this specific localization of nicotinic receptors. This review summarizes the current knowledge about formation and stabilization of the postsynaptic apparatus at the neuromuscular junction and extends this to explore the synaptic structures of interneuronal cholinergic synapses.

Single-Molecule Atomic Force Microscopy Reveals Clustering of the Yeast Plasma-Membrane Sensor Wsc1

“…We propose that stretching of either the cell wall or the plasma membrane will alter the conformation of the CRD domain, thereby exposing interfaces promoting intermolecular protein-protein interactions and triggering the association of further sensor molecules within the plasma membrane. In analogy to bacterial two-component sensor kinases [30] and receptor tyrosine kinases in higher eukaryotes [34], this could alter the phosphorylation state of the Wsc1 cytoplasmic domain and thus its interaction with the following signalling component Rom2 [35].…”

Morphological Regeneration and Functional Recovery of Neuromuscular Junctions after Tourniquet-Induced Injuries in Mouse Hindlimb

“…Efficient neuromuscular transmission is highly reliable, in that a high density of postsynaptic nAChRs (about 10,000 receptors/μm 2 ) is maintained in the motor endplate (Sanes and Lichtman, 2001) and redistributed to form nAChR clusters (Froehner et al, 1990; Phillips et al, 1991; Yu and Hall, 1994; Huh and Fuhrer, 2002). These compacted nAChR clusters are considered as safety mechanism in that the excess depolarization of the postsynaptic membrane in response to each nerve impulse ensures the occurrence of skeletal muscle contractions in healthy tissue (Wood and Slater, 2001).…”

Optogenetic studies of nicotinic contributions to cholinergic signaling in the central nervous system

“…Direct postsynaptic nicotinic currents were found in hippocampal interneurons by electrical stimulation of cholinergic inputs more than a decade ago (e.g., Alkondon et al, 1998; Jones et al, 1999; Huh and Fuhrer, 2002; Klein and Yakel, 2006 ; Dunant et al, 2010 ). More recent studies of transgenic models of green fluorescent protein (GFP)-expressing cholinergic neurons have also convincingly demonstrated direct synaptic transmission of cholinergic inputs to pyramidal neurons in the hippocampus (Grybko et al, 2011).…”

“…In the CNS, ACh release sites that are in close proximity to target nicotinic receptor pools characteristic of classical synapses have been difficult to demonstrate (but see Jones and Yakel, 1997; Alkondon et al, 1998; Frazier et al, 1998; Jones et al, 1999; Huh and Fuhrer, 2002; Klein and Yakel, 2006; Dunant et al, 2010). ACh released from ‘en passant’ cholinergic axons appears to interact with receptors localized on presynaptic terminals (i.e., axo-axonic synapses) and in preterminal zones as well as on perisynaptic or more traditional postsynaptic sites along dendrites (see Picciotto et al, 2012 for recent review and references therein).…”