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J. Biol. Chem., Vol. 269, Issue 45, 27811-27814, 11, 1994

Protein-tyrosine phosphatases specifically regulate muscle adult-type nicotinic acetylcholine receptor gene expression

MK Sapru, G Zhou and D Goldman
Mental Health Research Institute, University of Michigan, Ann Arbor 48109.

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.
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