Activation of calcium-dependent potassium channels in rat brain neurons by neurotrophin-3 and nerve growth factor
Activation of calcium-dependent potassium channels in rat brain neurons by neurotrophin-3 and nerve growth factor
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DOI：
10.1073/pnas.94.3.1002
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发表时间：
1997-02-04
影响因子：
11.1
通讯作者：
Gammeltoft, S
中科院分区：
文献类型：
--
作者：
Holm, NR;Christophersen, P;Gammeltoft, S
神经营养因子是神经系统发育和再生过程中不同神经元群体存活和分化所必需的信号传导因子。神经营养因子的长期作用已被详细研究，但对它们对神经元活性的急性作用知之甚少。在这里，我们使用透性全细胞膜片钳证明，神经营养因子-3（NT-3）和神经生长因子激活钙依赖性，paxilline敏感性钾通道（BK通道）在皮层神经元。应用NT-3或神经生长因子可使BK电流迅速而缓慢地增加，并持续30-50 min;脑源性神经营养因子、睫状神经营养因子和胰岛素样生长因子-1无显著影响，对NT-3的反应被蛋白激酶、磷脂酶C和丝氨酸/苏氨酸蛋白磷酸酶1和2a的抑制剂阻断，从细胞外介质中省略Ca 2+阻止NT-3的作用。我们的研究结果表明，NT-3通过涉及Trk酪氨酸激酶、磷脂酶C和蛋白质去磷酸化且具有钙依赖性的信号通路刺激皮质神经元中的BK通道活动。BK通道的激活可能是神经营养因子急性调节神经元活动的主要机制。
The neurotrophins are signaling factors that are essential for survival and differentiation of distinct neuronal populations during the development and regeneration of the nervous system. The long-term effects of neurotrophins have been studied in detail, but little is known about their acute effects on neuronal activity. Here we use permeabilized whole-cell patch clamp to demonstrate that neurotrophin-3 (NT-3) and nerve growth factor activate calcium-dependent, paxilline-sensitive potassium channels (BK channels) in cortical neurons. Application of NT-3 or nerve growth factor produced a rapid and gradual rise in BK current that was sustained for 30-50 min; brain-derived neurotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor-1 had no significant effect, The response to NT-3 was blocked by inhibitors of protein kinases, phospholipase C, and serine/threonine protein phosphatase 1 and 2a, Omission of Ca2+ from the extracellular medium prevented the NT-3 effect. Our results indicate that NT-3 stimulates BK channel activity in cortical neurons through a signaling pathway that involves Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent. Activation of BK channels may be a major mechanism by which neurotrophins acutely regulate neuronal activity.