Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor
Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor
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DOI：
10.1038/nature03477
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发表时间：
2005-04-14
期刊：
影响因子：
64.8
通讯作者：
Yuan, XB
中科院分区：
文献类型：
--
作者：
Li, Y;Jia, YC;Yuan, XB
已知脑源性神经营养因子（BDNF）促进神经元存活和分化（1），并在体外（2，3）和体内（4）指导轴突延伸。BDNF诱导的轴突生长锥的化学吸引需要Ca2+信号传导（3），但在生长锥中BDNF如何调节Ca2+仍不清楚。BDNF的细胞外应用触发类似于通过大鼠脑桥神经元（5）和非洲爪蟾脊髓神经元（6）中的TRPC（瞬时受体电位典型）通道的膜电流。在这里，我们报告说，在培养的小脑颗粒细胞，TRPC通道有助于BDNF诱导的生长锥中的Ca2+的升高，并需要BDNF诱导的化学吸引转向。TRPC家族的几个成员在这些神经元中高度表达，并且由BDNF诱导的Ca2+升高和生长锥转动都通过TRPC通道的药理学抑制、TRPC 3或TRPC 6的显性负性形式的过表达或通过短干扰RNA下调TRPC 3表达而被消除。因此，TRPC通道活性对于BDNF引导神经生长锥是必不可少的。
Brain-derived neurotrophic factor ( BDNF) is known to promote neuronal survival and differentiation(1) and to guide axon extension both in vitro(2,3) and in vivo(4). The BDNF-induced chemoattraction of axonal growth cones requires Ca2+ signalling(3), but how Ca2+ is regulated by BDNF at the growth cone remains largely unclear. Extracellular application of BDNF triggers membrane currents resembling those through TRPC ( transient receptor potential canonical) channels in rat pontine neurons(5) and in Xenopus spinal neurons(6). Here, we report that in cultured cerebellar granule cells, TRPC channels contribute to the BDNF-induced elevation of Ca2+ at the growth cone and are required for BDNF-induced chemo-attractive turning. Several members of the TRPC family are highly expressed in these neurons, and both Ca2+ elevation and growth-cone turning induced by BDNF are abolished by pharmacological inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 or TRPC6, or downregulation of TRPC3 expression via short interfering RNA. Thus, TRPC channel activity is essential for nerve-growth-cone guidance by BDNF.