Lipid Rafts Serve as a Signaling Platform for Nicotinic Acetylcholine Receptor Clustering

Abstract

Agrin, a motoneuron-derived factor, and the muscle-specific receptor tyrosine kinase (MuSK) are essential for the acetylcholine receptor (AChR) clustering at the postjunctional membrane. However, the underlying signaling mechanisms remain poorly defined. We show that agrin stimulates a dynamic translocation of the AChR into lipid rafts-cholesterol and sphingolipid-rich microdomains in the plasma membrane. This follows MuSK partition into lipid rafts and requires its activation. Disruption of lipid rafts inhibits MuSK activation and downstream signaling and AChR clustering in response to agrin. Rapsyn, an intracellular protein necessary for AChR clustering, is located constitutively in lipid rafts, but its interaction with the AChR is inhibited when lipid rafts are perturbed. These results reveal that lipid rafts may regulate AChR clustering by facilitating the agrin/MuSK signaling and the interaction between the receptor and rapsyn, both necessary for AChR clustering and maintenance. These results provide insight into mechanisms of AChR cluster formation.

Identification of Erbin Interlinking MuSK and ErbB2 and Its Impact on Acetylcholine Receptor Aggregation at the Neuromuscular Junction

“…Possibly, lipid rafts regulate AChR clustering by facilitating agrin-MuSK signaling and thereby promote the interaction between AChRs and rapsyn (Zhu et al, 2006). Erbin might be involved in this regulation by colocalizing MuSK, ErbB2, and AChRs at lipid rafts for signaling at the NMJ.…”

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

“…Signaling via the agrin/MuSK complex and interaction between the receptor and rapsyn appears to involve Lo-type lipid platforms [154]. The formation of micron-sized nAChR clusters induced by agrin in muscle cells has been found to be influenced by cholesterol [29].…”

“…Another study [146] proposed that these cholesterol-rich lipid microdomains and Src-family kinases both contribute to stabilizing nAChRs and the postsynaptic apparatus. A pool of nAChRs has indeed been found in Lo domains in mammalian cells [27,29,80,127,146,154]. In contrast, when reconstituted in a sphingomyelin-cholesterol-POPC (1:1:1) model system, purified nAChR protein from Torpedo was found not to exhibit any preference for Lo domains in vitro [17].…”

Molecular and structural bases for postsynaptic signal processing: interaction between postsynaptic density and postsynaptic membrane rafts

“…46 Additional evidence that supports raft association of non-type I synapses includes palmitoylation of GABA A receptors, 47 effects of cholesterol depletion on GABA A receptor β2/3 subunit cluster distribution, 48 and the presence and roles of membrane rafts at neuromuscular junctions. 49 Membrane raft …”

“…43,61,104 Involvement of membrane rafts in central nervous system synaptogenesis is also suggested in a mechanism for AChR clustering, an early event of synaptogenesis of the neuromuscular junction. 49,105,106 Targeting to the neuromuscular junction of AChRs and rapsyn, which is necessary for AChR clustering, appears to be mediated by membrane rafts. 107 Finally, membrane rafts regulate formation of immunological synapses (ISs), 97 which possibly share common structural and functional properties and mechanisms with neuronal synapses as cell-cell contact sites (see following section).…”