Xiong H, Futamura T, Jourdi H, Zhou H, Takei N, Diverse-Pierluissi M, Plevy S, Nawa H
Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
Neuropharmacology. 2002 Jun;42(7):903-12. doi: 10.1016/s0028-3908(02)00043-6.
Neurotrophins jointly exert various functions in the nervous system, including neuronal differentiation, survival, and regulation of synaptic plasticity. However, the functional interactions of neurotrophins or mechanisms through which neurotrophins regulate each other are still not clear. In the present study, brain-derived neurotrophic factor (BDNF) mRNA expression is induced by neurotrophin-4/5 (NT-4/5) and by BDNF itself in neocortical neurons. K252a, a specific tyrosine kinase (Trk) inhibitor, completely suppresses BDNF- and NT-4/5-enhanced BDNF mRNA expression. NT-4/5 significantly augments BDNF protein production, which is also reversed by K252a. When neurons are incubated with neurotrophin-3 (NT-3) or nerve growth factor (NGF), there are no significant changes in BDNF mRNA or protein expression. Interestingly, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the N-methyl-D-aspartate (NMDA) receptor blocker AP-5 completely suppresses NT-4/5-enhanced BDNF protein production, while tetrodotoxin (TTX) only suppresses NT-4/5-enhanced BDNF production by 50%. Additionally, the mitogen activated protein (MAP) kinase inhibitor PD98059 enhances BDNF-induced glutamate receptor-1 (GluR1) protein expression, but a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 strongly reduces BDNF-induced GluR1 protein expression. Taken together, glutamate receptors are important for the regulation of BDNF expression by neurotrophins, and MAP and PI3K kinases differentially modulate AMPA receptor expression in the cortical neurons.
神经营养因子在神经系统中共同发挥多种功能，包括神经元分化、存活以及突触可塑性的调节。然而，神经营养因子的功能相互作用或其相互调节的机制仍不清楚。在本研究中，脑源性神经营养因子（BDNF）mRNA表达在新皮质神经元中由神经营养因子-4/5（NT-4/5）和BDNF自身诱导产生。K252a，一种特异性酪氨酸激酶（Trk）抑制剂，完全抑制BDNF和NT-4/5增强的BDNF mRNA表达。NT-4/5显著增加BDNF蛋白的产生，这也被K252a逆转。当神经元与神经营养因子-3（NT-3）或神经生长因子（NGF）孵育时，BDNF mRNA或蛋白表达没有显著变化。有趣的是，α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体阻滞剂6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）或N-甲基-D-天冬氨酸（NMDA）受体阻滞剂AP-5完全抑制NT-4/5增强的BDNF蛋白产生，而河豚毒素（TTX）仅抑制NT-4/5增强的BDNF产生的50%。此外，丝裂原活化蛋白（MAP）激酶抑制剂PD98059增强BDNF诱导的谷氨酸受体-1（GluR1）蛋白表达，但磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002强烈降低BDNF诱导的GluR1蛋白表达。综上所述，谷氨酸受体对于神经营养因子调节BDNF表达很重要，并且MAP和PI3K激酶在皮质神经元中对AMPA受体表达有不同的调节作用。
