p75 and TrkA signaling regulates sympathetic neuronal firing patterns via differential modulation of voltage-gated currents.
p75 and TrkA signaling regulates sympathetic neuronal firing patterns via differential modulation of voltage-gated currents.
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DOI：
10.1523/jneurosci.3503-08.2009
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发表时间：
2009-04-29
期刊：
影响因子：
--
通讯作者：
Birren SJ
中科院分区：
文献类型：
--
作者：
Luther JA;Birren SJ
神经营养因子如神经生长因子（NGF）和脑源性神经营养因子（BDNF）通过原肌球蛋白相关受体酪氨酸激酶（Trk）和泛神经营养因子受体（p75）起作用以调节神经元的复杂发育和功能特性。虽然NGF激活交感神经元中的两种受体类型，但通过TrkA和p75的差异信号传导可导致神经元存活、生长和突触功能的广泛不同的功能输出。在这里，我们表明，TrkA和p75信号传导对交感神经元的放电特性有相反的影响，并定义了一种机制，即通过这两个受体的信号传导的相对水平通过一组离子电流的协调调节来设置放电模式。我们发现，通过p75通路的信号传导导致交感神经元发射的相位模式显示显着的住宿。另一方面，通过NGF特异性TrkA的信号传导导致细胞紧张性地放电。神经元在放电模式之间快速切换，大约几分钟到几小时。我们发现，放电模式的变化是由神经营养依赖性调节至少四个电压门控电流;钠电流和M型，延迟整流和钙依赖性钾电流。神经营养因子的释放以及因此受体的激活在躯体组织和生理状态之间变化。因此，这些数据表明，靶源性神经营养因子可能是交感神经元的特征性电特性的重要决定因素，并因此调节交感神经系统的功能输出。
Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) act through the tropomyosin-related receptor tyrosine kinases (Trk) and the pan-neurotrophin receptor (p75) to regulate complex developmental and functional properties of neurons. While NGF activates both receptor types in sympathetic neurons, differential signaling through TrkA and p75 can result in widely divergent functional outputs for neuronal survival, growth, and synaptic function. Here we show that TrkA and p75 signaling have opposing effects on the firing properties of sympathetic neurons, and define a mechanism whereby the relative level of signaling through these two receptors sets firing patterns via coordinate regulation of a set of ionic currents. We show that signaling through the p75 pathway causes sympathetic neurons to fire in a phasic pattern showing marked accommodation. Signaling through the NGF-specific TrkA on the other hand causes cells to fire tonically. Neurons switch rapidly between firing patterns, on the order of minutes to hours. We show that changes in firing patterns are caused by neurotrophin-dependent regulation of at least four voltage-gated currents; the sodium current and the M-type, delayed rectifier and calcium-dependent potassium currents. Neurotrophin release, and thus receptor activation, varies among somatic tissues and physiological state. Thus, these data suggest that target-derived neurotrophins may be an important determinant of the characteristic electrical properties of sympathetic neurons and therefore regulate the functional output of the sympathetic nervous system.