Sapru M K, Zhou G, Goldman D
Mental Health Research Institute, University of Michigan, Ann Arbor 48109.
J Biol Chem. 1994 Nov 11;269(45):27811-4.
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.
骨骼肌的神经支配导致神经肌肉接头下方成年型烟碱型乙酰胆碱受体（α2βεδ）的表达。这种局部表达很大程度上是终板相关肌细胞核中成年型烟碱型乙酰胆碱受体（nAChR）基因选择性诱导的结果。神经诱导这些细胞核中基因表达的分子机制尚不清楚。我们之前已经表明，离子载体诱导的钙流入质膜会优先降低成年型特异性nAChR ε亚基基因的表达（Walke, W., Staple, J., Adams, L., Gnegy, M., Chahine, K., and Goldman, D. (1994) J. Biol. Chem. 269, 19447 - 19456）。在此我们提供证据表明，编码成年型nAChRs的基因受到蛋白酪氨酸磷酸酶活性的特异性调节。原钒酸盐是一种特异性蛋白酪氨酸磷酸酶抑制剂，它能使大鼠原代肌管中ε亚基基因的表达增加，并能够完全阻断钙流入增加对ε亚基RNA表达的抑制作用。蛋白酪氨酸磷酸酶的过表达选择性地降低了成年型nAChR基因的表达，而对胚胎型特异性γ亚基基因没有影响。这些结果表明蛋白酪氨酸磷酸酶调节哺乳动物成年型nAChR基因的表达，并提示了一种肌肉神经支配选择性调节终板相关肌细胞核中基因表达的机制。
