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首页> 外文期刊>Molecular and Cellular Biology >Analysis of mutant platelet-derived growth factor receptors expressed in PC12 cells identifies signals governing sodium channel induction during neuronal differentiation.
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Analysis of mutant platelet-derived growth factor receptors expressed in PC12 cells identifies signals governing sodium channel induction during neuronal differentiation.

机译：分析PC12细胞中表达的突变型血小板衍生生长因子受体，可以识别在神经元分化过程中控制钠通道诱导的信号。

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摘要

The mechanisms governing neuronal differentiation, including the signals underlying the induction of voltage-dependent sodium (Na+) channel expression by neurotrophic factors, which occurs independent of Ras activity, are not well understood. Therefore, Na+ channel induction was analyzed in sublines of PC12 cells stably expressing platelet-derived growth factor (PDGF) beta receptors with mutations that eliminate activation of specific signalling molecules. Mutations eliminating activation of phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma (PLC gamma), the GTPase-activating protein (GAP), and Syp phosphatase failed to diminish the induction of type II Na+ channel alpha-subunit mRNA and functional Na+ channel expression by PDGF, as determined by RNase protection assays and whole-cell patch clamp recording. However, mutation of juxtamembrane tyrosines that bind members of the Src family of kinases upon receptor activation inhibited the induction of functional Na+ channels while leaving the induction of type II alpha-subunit mRNA intact. Mutation of juxtamembrane tyrosines in combination with mutations eliminating activation of PI3K, PLC gamma, GAP, and Syp abolished the induction of type II alpha-subunit mRNA, suggesting that at least partially redundant signaling mechanisms mediate this induction. The differential effects of the receptor mutations on Na+ channel expression did not reflect global changes in receptor signaling capabilities, as in all of the mutant receptors analyzed, the induction of c-fos and transin mRNAs still occurred. The results reveal an important role for the Src family in the induction of Na+ channel expression and highlight the multiplicity and combinatorial nature of the signaling mechanisms governing neuronal differentiation.
机译：尚未完全了解控制神经元分化的机制，包括神经营养因子诱导电压依赖性钠（Na +）通道表达的信号，这些信号独立于Ras活性而发生。因此，在稳定表达血小板源性生长因子（PDGF）β受体的PC12细胞亚系中分析了Na +通道诱导，其突变消除了特定信号分子的激活。消除磷脂酰肌醇3激酶（PI3K），磷脂酶Cγ（PLCγ），GTPase激活蛋白（GAP）和Syp磷酸酶激活的突变未能减少对II型Na +通道α-亚基mRNA和功能性Na +通道的诱导通过RNase保护测定和全细胞膜片钳记录确定PDGF的表达。但是，受体激活后结合激酶Src家族成员的近膜酪氨酸突变抑制了功能性Na +通道的诱导，而完整地诱导了II型α-亚基mRNA。近膜酪氨酸突变与消除PI3K，PLCγ，GAP和Syp激活的突变相结合，消除了对II型α-亚基mRNA的诱导，这表明至少部分冗余的信号传导机制介导了这种诱导。受体突变对Na +通道表达的差异影响并未反映出受体信号传导能力的整体变化，因为在所有分析的突变受体中，仍会诱导c-fos和transin mRNA。结果揭示了Src家族在诱导Na +通道表达中的重要作用，并强调了控制神经元分化的信号传导机制的多重性和组合性。

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