Distribution of 5-ht1E receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study
Distribution of 5-ht1E receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study
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DOI：
10.1111/j.1476-5381.2012.01868.x
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发表时间：
2012-06-01
影响因子：
7.3
通讯作者：
Teitler, M.
中科院分区：
文献类型：
--
作者：
Klein, M. T.;Teitler, M.
背景和目的5-ht 1 E受体在人脑中高度表达，并且其结构在人体中是保守的，这表明5-ht 1 E受体具有重要的生理作用。然而，这种受体的功能和分布在哺乳动物脑中的特点还没有得到证实。实验方法大鼠和小鼠缺乏5-ht 1 E受体基因，因此，我们使用豚鼠脑组织和免疫荧光染色技术，以提供第一个特定的5-ht 1 E受体在哺乳动物大脑中的定位。在嗅球肾小球以及齿状回（DG）的分子层中检测到高水平的5-ht 1 E受体。在DG膜中，BRL 54443（一种5-ht 1 E/5-HT 1F激动剂）选择性刺激5-ht 1 E受体并有效抑制毛喉素依赖性cAMP的产生（IC 50 = 14 nM）。脑组织中5-ht 1 E受体的染色模式表明，该受体主要在神经元中表达，而不是在神经胶质中表达。此外，5-ht 1 E受体在脑动脉的外膜层中检测到，但在微血管、静脉组织或其他脑动脉中未检测到。结论：这些观察结果有助于预测5-HT 1 E选择性药物的临床疗效。例如，DG中5-ht 1 E受体的刺激和随后腺苷酸环化酶活性的抑制表明5-ht 1 E受体可能介导5-HT对海马活动的调节，使其成为治疗以记忆缺陷为特征的神经精神疾病（如阿尔茨海默病）的可能药物靶点或作为治疗颞叶癫痫的靶点。
BACKGROUND AND PURPOSE The 5-ht1E receptor is highly expressed in the human brain and its structure is conserved in humans, suggesting an important physiological role for 5-ht1E receptors. However, neither the function nor the distribution of this receptor has been characterized in the mammalian brain. EXPERIMENTAL APPROACH Rats and mice lack the 5-ht1E receptor gene; thus, we used guinea pig brain tissue and immunofluorescent staining techniques to provide the first specific localization of 5-ht1E receptors in the mammalian brain. KEY RESULTS High levels of 5-ht1E receptors are detected in olfactory bulb glomeruli as well as the molecular layer of the dentate gyrus (DG). In DG membranes, BRL54443, a 5-ht1E/5-HT1F agonist, selectively stimulated 5-ht1E receptors and potently inhibited forskolin-dependent cAMP production (IC50= 14 nM). The staining pattern of 5-ht1E receptors in brain tissue suggests that this receptor is expressed predominantly in neurons rather than in glia. Additionally, 5-ht1E receptors were detected in the adventitial layer of cerebral arteries but not in the microvasculature, venous tissue or other brain arteries. CONCLUSIONS AND IMPLICATIONS These observations should help to predict clinical effects of 5-ht1E-selective drugs. For example, the stimulation of 5-ht1E receptors and subsequent inhibition of adenylate cyclase activity in the DG suggests that 5-ht1E receptors may mediate regulation of hippocampal activity by 5-HT, making it a possible drug target for the treatment of neuropsychiatric disorders characterized by memory deficits (such as Alzheimer's disease) or as a target for the treatment of temporal lobe epilepsy.