Neuregulin inhibits acetylcholine receptor aggregation in myotubes.
The high local concentration of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction results from their aggregation by the agrin/MuSK signaling pathway and their synthetic up-regulation by the neuregulin/ErbB pathway. Here, we show a novel role for the neuregulin/ErbB pathway, the inhibition of AChR aggregation on the muscle surface. Treatment of C2C12 myotubes with the neuregulin epidermal growth factor domain decreased the number of both spontaneous and agrin-induced AChR clusters, in part by increasing the rate of cluster disassembly. Upon cluster disassembly, AChRs were internalized into caveolae (as identified by caveolin-3). Time-lapse microscopy revealed that individual AChR clusters fragmented into puncta, and application of neuregulin accelerated the rate at which AChR clusters decreased in area without affecting the density of AChRs remaining in individual clusters (as measured by the fluorescence intensity/unit area). We propose that this novel action of neuregulin regulates synaptic competition at the developing neuromuscular junction.
Trinidad
Jonathan C
JC
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cohen
Jonathan B
JB
D018171:Agrin / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D018739:Oncogene Proteins v-erbB / Q000378:metabolism; D051381:Rats; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism
D018171:Agrin; C495548:Cav3 protein, mouse; C495549:Cav3 protein, rat; D051244:Caveolin 3; D022461:Caveolins; D004268:DNA-Binding Proteins; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C117467:neuregulin beta