DIFFERENTIAL USAGE OF MULTIPLE BRAIN-DERIVED NEUROTROPHIC FACTOR PROMOTERS IN THE RAT-BRAIN FOLLOWING NEURONAL ACTIVATION
DIFFERENTIAL USAGE OF MULTIPLE BRAIN-DERIVED NEUROTROPHIC FACTOR PROMOTERS IN THE RAT-BRAIN FOLLOWING NEURONAL ACTIVATION
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DOI：
10.1073/pnas.90.19.8802
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发表时间：
1993-10-01
影响因子：
11.1
通讯作者：
PERSSON, H
中科院分区：
文献类型：
--
作者：
METSIS, M;TIMMUSK, T;PERSSON, H
大鼠脑源性神经营养因子（BDNF）基因由4个5‘外显子和1个3’外显子组成，外显子连接不同的启动子，外显子编码BDNF前原蛋白。为了深入了解BDNF mRNA的表达调控，我们使用了针对不同5'外显子的探针来研究脑内BDNF mRNA的表达。在全身注射谷氨酸类似物kainic酸后，海马和大脑皮层的外显子I、II和III mrna短暂增加。外显子IV中出现了适度的增加，其中一个新的转录起始位点被这种治疗诱导。用n-甲基-d -天冬氨酸（NMDA）受体拮抗剂MK801或α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂2,3-二羟基-6-硝基磺酰苯并(f)喹啉进行预处理，揭示了谷氨酸受体介导的两种区域特异性调节模式。在新皮质、梨状皮质和杏仁核中发现的第一种模式涉及通过NMDA和AMPA/kainate受体调节BDNF外显子I、II和III mrna。在海马中发现的第二种模式涉及高亲和力的盐酸盐或代谢代谢受体对BDNF外显子I、II和III mrna的调节。γ -氨基丁酸亚型A（GABA(A)）受体拮抗剂双丘碱增加齿状回外显子I和III mRNA，毒毒碱受体激动剂匹洛卡平增加主要在新皮层的外显子I mRNA。这些数据表明，四种BDNF启动子允许BDNF mRNA的多点调控，并提示不同亚型谷氨酸受体的激活差异调节脑内BDNF外显子特异性mRNA的表达。
The rat brain-derived neurotropic factor (BDNF) gene consists of four 5' exons linked to separate promoters and one 3' exon encoding the prepro-BDNF protein. To gain insights into the regulation of BDNF mRNA expression, probes specific for the different 5' exons were used to study the expression of BDNF mRNA in the brain. Following a systemic injection of the glutamate analog kainic acid, exon I, II, and III mRNAs increased transiently in hippocampus and cerebral cortex. A modest increase was seen for exon IV, where a new transcription initiation site was induced by this treatment. Pretreatments with the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 or the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitrosulfanoylbenzo(f)quinoxaline revealed two region-specific patterns of glutamate receptor-mediated regulation. The first pattern found in neocortex, piriform cortex, and amygdala involves regulation of BDNF exon I, II, and III mRNAs through NMDA and AMPA/kainate receptors. The second pattern found in the hippocampus involves regulation of BDNF exon I, II, and III mRNAs by high-affinity kainate or metabotropic receptors. Treatment with the gamma-aminobutyric acid subtype A (GABA(A)) receptor antagonist bicuculline increased exon I and III mRNAs in the dentate gyrus, and the muscarinic receptor agonist pilocarpine increased exon I mRNA mainly in the neocortex. These data show that the four BDNF promoters allow multiple points of BDNF mRNA regulation and suggest that the activation of different subtypes of glutamate receptors differentially regulates the expression of BDNF exon-specific mRNAs in the brain.