Protein-tyrosine phosphatases specifically regulate muscle adult-type nicotinic acetylcholine receptor gene expression.
Innervation of skeletal muscles results in expression of adult-type nicotinic acetylcholine receptors (alpha 2 beta epsilon delta) beneath the neuromuscular junction. This local expression is largely a result of selective induction of adult-type nicotinic acetylcholine receptor (nAChR) genes in endplate-associated myonuclei. The molecular mechanism by which the nerve induces gene expression in these nuclei is not known. We have shown previously that ionophore-induced calcium influx across the plasma membrane preferentially decreases expression from the adult-type specific nAChR epsilon-subunit gene (Walke, W., Staple, J., Adams, L., Gnegy, M., Chahine, K., and Goldman, D. (1994) J. Biol. Chem. 269, 19447-19456). Here we provide evidence that the genes encoding adult-type nAChRs are specifically regulated by protein-tyrosine phosphatase activity. Orthovanadate, a specific protein-tyrosine phosphatase inhibitor, caused increased expression of the epsilon-subunit gene in rat primary myotubes and was able to completely block the suppressive effects of increased calcium influx on epsilon-subunit RNA expression. Overexpression of protein-tyrosine phosphatases selectively decreased expression from the adult-type nAChR genes with no effect on the embryonic-type specific gamma-subunit gene. These results demonstrate that protein-tyrosine phosphatases regulate mammalian adult-type nAChR gene expression and suggest a mechanism by which muscle innervation selectively regulates gene expression in endplate-associated myonuclei.
Mental Health Research Institute, University of Michigan, Ann Arbor 48109.
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D000375:Aging; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D004625:Embryo, Nonmammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D009045:Motor Endplate / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D014638:Vanadates / Q000494:pharmacology
D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D000001:Calcimycin; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases; D002118:Calcium