Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Abstract

SummaryAt neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signalling through the muscle-specific kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act through muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1-ErbB signalling can modulate n-agrin-induced AChR clustering independently of its effects on transcription.Here we report that neuregulin-1 increased the size of developing AChR clusters when injected into muscles of embryonic mice. We investigated this phenomenon using cultured myotubes, and found that in the ongoing presence of n-agrin, neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. This potentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK. Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence might function as a second-order regulator of postsynaptic AChR clustering at the neuromuscular synapse. Thus two classic synaptic signalling systems (neuregulin-1 and n-agrin) converge upon MuSK to regulate postsynaptic differentiation.

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

“…As such, antibodies that inhibit MuSK function would be expected to disrupt the architecture of the neuromuscular synapse as well as perturb neurotransmitter release and reception (9,18,19,34,(41)(42)(43)(44). Because the synaptic accumulation of acetylcholinesterase (AChE), like all other postsynaptic proteins, depends on MuSK (10,42), IgG4 antibodies to MuSK are likely to lower AChE expression at the synapse, which may explain the hypersensitivity of MuSK MG patients to AChE inhibitors.…”

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…Exploring use of this drug, which enhances AChR release at the motor nerve terminal, in MuSK MG is supported by preclinical models, experience with congenital MG with MuSK mutations, and case reports [152,153]. Other endplate targets with potential therapeutic application in MG include agrin potentiators and positive allosteric modulators of the skeletal muscle AChR [154,155].…”

Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation

“…Nrg1 contributes to axonal regeneration and normal myelination in mice (Stassart et al, 2012) through its effects on Schwann cells, whereas silencing of Nrg1 impairs axonal regeneration (Fricker et al, 2011). It also plays an important role in NMJ maintenance (Wolpowitz et al, 2000) by regulating multiple aspects of Schwann cell differentiation, proliferation, motility, and myelination (Esper et al, 2006) and promoting acetylcholine receptor clustering at the NMJ during development (Ngo et al, 2012). Nrg1 increases terminal Schwann cells survival after postnatal denervation and promotes process extension required for new NMJ formation (Trachtenberg and Thompson, 1996;Hayworth et al, 2006).…”