Gupta Manveen K, Papay Robert S, Jurgens Chris W D, Gaivin Robert J, Shi Ting, Doze Van A, Perez Dianne M
Department of Molecular Cardiology, NB50, the Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Mol Pharmacol. 2009 Aug;76(2):314-26. doi: 10.1124/mol.109.057307. Epub 2009 Jun 1.
The understanding of the function of alpha(1)-adrenergic receptors in the brain has been limited due to a lack of specific ligands and antibodies. We circumvented this problem by using transgenic mice engineered to overexpress either wild-type receptor tagged with enhanced green fluorescent protein or constitutively active mutant alpha(1)-adrenergic receptor subtypes in tissues in which they are normally expressed. We identified intriguing alpha(1A)-adrenergic receptor subtype-expressing cells with a migratory morphology in the adult subventricular zone that coexpressed markers of neural stem cell and/or progenitors. Incorporation of 5-bromo-2-deoxyuridine in vivo increased in neurogenic areas in adult alpha(1A)-adrenergic receptor transgenic mice or normal mice given the alpha(1A)-adrenergic receptor-selective agonist, cirazoline. Neonatal neurospheres isolated from normal mice expressed a mixture of alpha(1)-adrenergic receptor subtypes, and stimulation of these receptors resulted in increased expression of the alpha(1B)-adrenergic receptor subtype, proneural basic helix-loop-helix transcription factors, and the differentiation and migration of neuronal progenitors for catecholaminergic neurons and interneurons. alpha(1)-Adrenergic receptor stimulation increased the apoptosis of astrocytes and regulated survival of neonatal neurons through phosphatidylinositol 3-kinase signaling. However, in adult normal neurospheres, alpha(1)-adrenergic receptor stimulation increased the expression of glial markers at the expense of neuronal differentiation. In vivo, S100-positive glial and betaIII tubulin neuronal progenitors colocalized with either alpha(1)-adrenergic receptor subtype in the olfactory bulb. Our results indicate that alpha(1)-adrenergic receptors can regulate both neurogenesis and gliogenesis that may be developmentally dependent. Our findings may lead to new therapies to treat neurodegenerative diseases.
由于缺乏特异性配体和抗体，对大脑中α(1)-肾上腺素能受体功能的了解一直有限。我们通过使用转基因小鼠来规避这个问题，这些小鼠经过基因工程改造，可在正常表达的组织中过表达标记有增强型绿色荧光蛋白的野生型受体或组成型活性突变α(1)-肾上腺素能受体亚型。我们在成年脑室下区发现了具有迁移形态的有趣的表达α(1A)-肾上腺素能受体亚型的细胞，这些细胞共表达神经干细胞和/或祖细胞的标志物。在成年α(1A)-肾上腺素能受体转基因小鼠或给予α(1A)-肾上腺素能受体选择性激动剂西拉唑啉的正常小鼠的神经发生区域，体内5-溴-2-脱氧尿苷的掺入增加。从正常小鼠分离的新生神经球表达多种α(1)-肾上腺素能受体亚型，刺激这些受体导致α(1B)-肾上腺素能受体亚型、神经前体碱性螺旋-环-螺旋转录因子的表达增加，以及儿茶酚胺能神经元和中间神经元的神经祖细胞的分化和迁移。α(1)-肾上腺素能受体刺激通过磷脂酰肌醇3-激酶信号传导增加星形胶质细胞的凋亡并调节新生神经元的存活。然而，在成年正常神经球中，α(1)-肾上腺素能受体刺激以神经元分化为代价增加了胶质细胞标志物的表达。在体内，嗅球中S100阳性胶质细胞和βIII微管蛋白神经元祖细胞与任一α(1)-肾上腺素能受体亚型共定位。我们的结果表明，α(1)-肾上腺素能受体可以调节神经发生和胶质发生，这可能具有发育依赖性。我们的发现可能会带来治疗神经退行性疾病的新疗法。
