CHARACTERIZATION OF GDNF ALPHA 1 (GFR ALPHA 1) RECEPTOR

GDNF ALPHA 1 (GFR ALPHA 1) 受体的特征

• 批准号: 6289615
• 负责人: BARRY J. HOFFER
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289615
• 关键词: GABA receptor; calcium binding protein; cell line; cell type; gene expression; genetic regulation; glutamine; growth factor receptors; hippocampus; interneurons; laboratory mouse; laboratory rat; neurotrophic factors; protein localization; pyramidal cells; substantia nigra; tissue /cell culture

The glial cell line-derived neurotrophic factor (GDNF) rescues motoneurons and nigral dopaminergic (DA) cells from induced cell death in different species of animals. In addition, GDNF results in a remarkable improvement of behavioral functions in Parkinsonian monkeys. A high affinity receptor for GDNF has been cloned (GFR alpha-1), whose pattern of expression indicates that it is not restricted to those brain areas containing motoneurons and DAergic cells, suggesting that GDNF might activate several sub-types of cells. To identify the phenotype of GFR alpha-1 expressing cells, we used a combination of anatomical techniques and found that GFRa-1 is expressed in defined populations of cells. We found that GFR alpha-1 is expressed in DAergic cells of the substantia nigra pars compacta (SNC), ventral tegmental area (VTA) and hypothalamus. We were able to establish that within the midbrain, GFR alpha-1 expression is not confined to dopaminergic neurons but is also expressed in GABAergic cells located either in the substantia nigra pars lateralis (SNL) or reticulata (SNR), being more abundant in the caudal levels of the SNR. These results suggest that GDNF-induced improvements in the behavior of semi-parkinsonian animal models might be also mediated by GDNF actions on GABAergic cells in the SNL and SNR. To test this hypothesis, we are processing brains from semi-parkisonian rats to analyze the levels of expression of GFR alpha- 1 and its relationship with the dopaminergic and GABAergic systems. Aside from the midbrain, we identified GFR alpha-1 expression in GABAergis cells located in the reticular thalamic nucleus, septum, cortex and hippocampus. While these results suggest the participation of the GDNF system in the regulation of dopaminergic and GABAergic functions, GDNF might also influence the cholinergic and serotonergic systems since expression of GFR alpha-1 was found in several septal cholinergic neurons and all serotonergic cells of the raphe nucleus. - GDNF, Substantia Nigra, Hippocampus, Neuroprotection

胶质细胞源性神经营养因子(GDNF)可使不同物种动物的运动神经元和黑质多巴胺能(DA)细胞免于细胞死亡。此外，GDNF还能显著改善帕金森病猴的行为功能。GDNF的高亲和力受体(GFRα-1)已被克隆，其表达模式表明它不局限于含有运动神经元和DAR能细胞的脑区，提示GDNF可能激活几种亚型的细胞。为了确定表达GFRα-1的细胞的表型，我们使用了解剖学技术的组合，发现GFRa-1在特定的细胞群中表达。我们发现GFRα-1在黑质致密部(SNC)、腹侧被盖区(VTA)和下丘脑的DAR能细胞中有表达。我们证实，在中脑，GFRα-1的表达不仅限于多巴胺能神经元，而且在位于黑质外侧部(SNL)或网状核(SNR)的GABA能细胞中也有表达，在SNR的尾部水平更为丰富。这些结果表明，GDNF对半帕金森病动物模型行为的改善可能也是通过GDNF对SNL和SNR内GABA能细胞的作用而实现的。为了验证这一假设，我们处理了半帕基斯病大鼠的大脑，分析了GFRα-1的表达水平及其与多巴胺和GABA能系统的关系。除了中脑，我们还发现GFRα-1在位于丘脑网状核、隔核、皮质和海马区的GABAergis细胞中表达。这些结果提示GDNF系统参与了多巴胺能和GABA能功能的调节，但GDNF也可能影响胆碱能和5-羟色胺能系统，因为GFRα-1在中缝核内的几个隔区胆碱能神经元和所有5-羟色胺能细胞中都有表达。-GDNF、黑质、海马体、神经保护