Lithium inhibits a late step in agrin-induced AChR aggregation.
Agrin activates an intracellular signaling pathway to induce the formation of postsynaptic specializations on muscle fibers. In myotubes in culture, this pathway has been shown to include autophosphorylation of the muscle-specific kinase MuSK, activation of Src-family kinases, tyrosine phosphorylation of the acetylcholine receptor (AChR) beta subunit, a decrease in receptor detergent extractability, and the accumulation of AChRs into high-density aggregates. Here we report that treating chick myotubes with lithium prevented any detectable agrin-induced change in AChR distribution without affecting the number of AChRs or the agrin-induced change in AChR tyrosine phosphorylation and detergent extractability. Lithium treatment also increased the rate at which AChR aggregates disappeared when agrin was removed. The effects of lithium developed slowly over the course of approximately 12 h. Thus, sensitivity to lithium identifies a late step in the agrin signaling pathway, after agrin-induced MuSK and AChR phosphorylation, that is necessary for the recruitment of AChRs into visible aggregates.
Sharma
S K
SK
Department of Physiology and Biophysics, C240, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Wallace
B G
BG
D018171:Agrin / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D002038:Bungarotoxins / Q000378:metabolism; D002642:Chick Embryo; D046508:Culture Techniques; D003598:Cytoskeletal Proteins / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005453:Fluorescence; D007211:Indoles / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011940:Receptor Aggregation / Q000187:drug effects* / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000187:drug effects; D051176:beta Catenin
D018171:Agrin; D001552:Benzazepines; D002038:Bungarotoxins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; D015534:Trans-Activators; C120793:alsterpaullone; D051176:beta Catenin; D008094:Lithium; C095714:MUSK protein, human; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C064758:Ro 31-8220