Pharmacology of neuronal nicotinic acetylcholine receptor subtypes.
Pharmacology of neuronal nicotinic acetylcholine receptor subtypes.
复制标题
DOI：
10.1016/s1054-3589(08)60072-1
复制
发表时间：
1997-01-01
期刊：
影响因子：
--
通讯作者：
Patrick, J W
中科院分区：
文献类型：
--
作者：
Colquhoun, L M;Patrick, J W
对大脑神经元上的尼古丁受体的生理功能的探索始于它们的发现。最初的假设是，就像在神经节和神经肌肉连接处一样，尼古丁受体会控制大脑中的快速突触传递。然而，目前最有效的功能证据表明，它在调节其他递质的释放方面起着作用。这并不排除尼古丁受体在大脑中传递的突触后作用，但试图定位这样一个突触尚未成功。如果大脑中存在快速尼古丁突触，它们的数量可能很低，并且可能被其他更普遍的突触（如谷氨酸突触）所掩盖，因此识别起来并不容易。烟碱受体的多样性程度是可观的。在分子水平上，这反映在编码受体亚基的不同基因的数量以及在表达系统中起作用的亚基的多种可能组合上。从细胞水平来看，神经元的天然受体具有广泛的多样性。一些有用的药理学工具允许对天然受体的亚基进行有限的鉴定。例如，甲虫毒素阻断可识别α 7、α 8或α 9亚基；胞氨酸对受体的激活表明是α 7或β 4亚基；神经元班加罗毒素阻滞识别出β 2亚基。尽管通过仔细使用这些试剂获得了识别的线索，但我们还不能根据表达研究评估的药理学特性识别任何天然受体的所有成分。当考虑到受体的药理学和生物物理特性时，在卵母细胞中测试的组合都不能完全模仿天然受体。造成这种差异的原因已经进行了详细的讨论；卵母细胞可能不能忠实地制造神经元烟碱受体。例如，它们可能在翻译后不能正确修饰蛋白质，或者它们可能允许在体内不发生的亚基组合。另一种可能性是，亚基的正确组合尚未在卵母细胞中进行过测试。免疫沉淀实验的数据表明，许多受体含有三种或更多不同的亚基。将三个或更多亚单位的组合注射到卵母细胞的进一步实验结果可能具有启发性。受体的多样性可以使亚型靶向到特定的位置。烟碱受体位于突触前、终末和细胞胞体上。位于神经支配轴突上的烟碱受体的功能可能是调节其他神经递质的释放。这是一个有吸引力的假设，尼古丁受体可能参与改变中枢突触的重量；然而，在任何描述过这种现象的地区都没有发现轴突接触的证据。迄今为止所描述的突触前受体在药理学上是独一无二的；因此，如果有不同亚型的尼古丁受体修饰不同递质的释放，它们可能提供一种用药物外源性修饰特定递质的释放的手段。关于大脑中的尼古丁受体，仍有许多基本的未解之谜。天然尼古丁受体的成分是什么？它们对神经元的作用是什么？尽管在突触前有明显的作用，那些位于体细胞上的功能是什么呢？与肌肉烟碱受体不同，神经元烟碱受体对钙具有高度渗透性，这可能对突触可塑性和发育具有重要意义。最后，为什么会有这样的多样性？(抽象TRANCATED)
The search for the physiological function of nicotinic receptors on neurons in the brain began with their discovery. It was initially assumed that, as in ganglia and at the neuromuscular junction, nicotinic receptors would gate fast synaptic transmission in the brain. The best functional evidence now, however, points to a role in modifying the release of other transmitters. This does not preclude a postsynaptic role in transmission for nicotinic receptors in the brain, but attempts to locate such a synapse have not been successful. If fast nicotinic synapses are present in the brain, they are probably low in number and may be masked by other more prevalent synapses (such as glutamatergic) so identification will not be easy. The extent of diversity of nicotinic receptors is substantial. At the molecular level this is reflected in the number of different genes that encode receptor subunits and the multiple possible combinations of subunits that function in expression systems. From the cellular level there is a broad diversity of properties of native receptors in neurons. Some useful pharmacological tools allow the limited identification of subunits in native receptors. For example, block by alpha-bungarotoxin identifies alpha 7, alpha 8, or alpha 9 subunits; activation of a receptor by cytisine indicates an alpha 7 or beta 4 subunit; and neuronal bungarotoxin block identifies a beta 2 subunit. Despite the clues to identity gained by careful use of these agents, we have not been able to identify all the components of any native receptor based on pharmacological properties assessed from expression studies. When both pharmacological and biophysical properties of a receptor are taken into consideration, none of the combinations tested in oocytes mimics native receptors exactly. The reason for this discrepancy has been debated at length; it is possible that oocytes do not faithfully manufacture neuronal nicotinic receptors. For example, they may not correctly modify the protein after translation or they may allow a combination of subunits that do not occur in vivo. Another possibility is that correct combinations of subunits have not yet been tested in oocytes. Data from immunoprecipitation experiments suggest that many receptors contain three or more different subunits. Results from further experiments injecting combinations of three or more subunits into oocytes may be enlightening. The diversity of receptors may allow targeting of subtypes to specific locations. Nicotinic receptors are located presynaptically, preterminally, and on the cell soma. The function of the nicotinic receptors located on innervating axons is presumably to modify the release of other neurotransmitters. It is an attractive hypothesis that nicotinic receptors might be involved in modifying the weight of central synapses; however, in none of the regions where this phenomenon has been described is there any evidence for axoaxonal contacts. The presynaptic receptors described so far are pharmacologically unique; therefore, if there are different subtypes of nicotinic receptors modifying the release of different transmitters, they may provide a means of exogenously modifying the release of a particular transmitter with drugs. There are still many basic unanswered questions about nicotinic receptors in the brain. What are the compositions of native nicotinic receptors? What is their purpose on neurons? Although there is clearly a role presynaptically, what is the function of those located on the soma? Neuronal nicotinic receptors are highly permeable to calcium, unlike muscle nicotinic receptors, and this may have important implications for roles in synaptic plasticity and development. Finally, why is there such diversity? (ABSTRACT TRANCATED)