Woodall A J, Richards M A, Turner D J, Fitzgerald E M
Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK.
Cell Calcium. 2008 Jun;43(6):562-75. doi: 10.1016/j.ceca.2007.10.001. Epub 2007 Nov 9.
Voltage-gated calcium channels (Ca(v)) are tonically up-regulated via Ras/extracellular signal-regulated kinase (ERK) signalling in sensory neurones. However, the mechanisms underlying the specificity of cellular response to this pathway remain unclear. Neurotrophic factors are attractive candidates to be involved in this process as they are key regulators of ERK signalling and have important roles in neuronal survival, development and plasticity. Here, we report that in rat dorsal root ganglion neurones, endogenous nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) and epidermal growth factor (EGF) are all involved in tonic ERK-dependent up-regulation of Ca(v) channels. Chronic (overnight) deprivation of growth factors inhibits total Ca(v) current according to developmental changes in expression of the cell surface receptors for NGF, GDNF and EGF. Whilst EGF specifically regulates transcriptional expression of Ca(v)s, NGF and GDNF also acutely modulate Ca(v) channels within a rapid ( approximately 10min) time-frame. These acute effects likely involve changes in the biophysical properties of Ca(v)s, including altered channel gating rather than changes in surface expression. Furthermore, NGF, GDNF and EGF differentially regulate specific populations of Ca(v)s. Thus, ERK-dependent regulation of Ca(v) activity provides an elegant and extremely flexible system with which to tailor calcium influx to discrete functional demands.
电压门控钙通道（Ca(v)）在感觉神经元中通过Ras/细胞外信号调节激酶（ERK）信号通路持续上调。然而，细胞对该通路反应特异性的潜在机制仍不清楚。神经营养因子是参与这一过程的有吸引力的候选者，因为它们是ERK信号通路的关键调节因子，并且在神经元存活、发育和可塑性中发挥重要作用。在此，我们报告在大鼠背根神经节神经元中，内源性神经生长因子（NGF）、胶质细胞源性神经营养因子（GDNF）和表皮生长因子（EGF）均参与Ca(v)通道的ERK依赖性持续上调。根据NGF、GDNF和EGF细胞表面受体表达的发育变化，长期（过夜）剥夺生长因子会抑制总Ca(v)电流。虽然EGF特异性调节Ca(v)的转录表达，但NGF和GDNF也在快速（约10分钟）时间范围内急性调节Ca(v)通道。这些急性效应可能涉及Ca(v)生物物理特性的变化，包括通道门控改变而非表面表达变化。此外，NGF、GDNF和EGF对Ca(v)的特定群体有不同的调节作用。因此，Ca(v)活性的ERK依赖性调节提供了一个优雅且极其灵活的系统，可根据离散的功能需求调整钙内流。
