ION CHANNELS, RECEPTORS AND SECOND MESSENGERS IN THE NERVOUS SYSTEM

受体激动剂和各种毒素调节离子通道和 产生第二信使，包括环核苷酸、肌醇 磷酸二酯，花生四烯酸前列腺素， 鞘氨醇和磷脂酸。钙、钠、钾和 镁离子通过离子通道转运或转运后 蛋白质可以引起释放过程的激活，收缩 蛋白质，腺苷和鸟苷环化酶，磷酸二酯酶，蛋白质 激酶、磷脂酶、三磷酸腺苷酶和其他酶。可调的 相互作用或“串话”发生在第二信使之间 系统和离子传输系统。鸡毒--来自一名海军陆战队队员 甲藻能激活独特的钙通道，而钙通道不会出现 与任何已知的钙通道相同，包括所谓的 钙释放激活钙通道(CRAC)。然而，两者 毛霉毒素和CRAC通道被某些特定的 咪唑类(SKF 96365、咪康唑、克霉唑)。两个频道都是 也被三氟拉嗪阻断，但还有许多其他药物 只阻断毛霉毒素激活的通道。洛哌丁胺是一种 最有效的毛霉毒素诱导的通道阻断剂，但会导致 明显增强通过CRAC-通道的钙内流 都是由于受体-，thapsigargin-，或 离子霉素诱导的IP3敏感的细胞内池的耗竭 钙存在于多种细胞类型中。洛哌丁胺的作用是独一无二的， 高度依赖于结构，不容易被咪唑逆转。 洛哌丁胺对细胞内钙离子水平无任何影响 如果CRAC频道尚未激活。洛哌丁胺不能增加 鞘氨醇引起的钙离子内流。因此，洛哌丁胺不会 增加鞘氨醇引起的钙内流也不会增加内流 通过L类钙通道吸收钙。咪唑类化合物，此外 阻断CRAC通道，导致钙释放和内流 HL60细胞。卡咪唑引起的药物流入最多，但更简单 卡咪唑的类似物没有任何作用。刺参生物碱引起这两个 竞争性和非竞争性地封锁尼古丁通道。 白藜芦醇是这些生物碱中最有效的成员。 神经元烟碱受体通道。表波西定的托烷类似物有 中枢烟碱受体通道的纳摩尔亲和力。 值得注意的是，N-苄基衍生物保持了激动剂活性。从一个 与一种中草药生物碱结构相关的一系列托烷类化合物 包公藤A，类似物6β-乙酰氧基托烷被证明是一种有效的 M受体激动剂，对M2受体有一定的选择性。其他 类似物似乎对M1受体具有选择性，因此， 可能在减少认知缺陷方面有潜力。

Receptors agonists and various toxins serve to modulate ion channels and generation of second messengers, including cyclic nucleotides, inositol phosphates diacylglycerides, arachidonic acid prostaglandins, sphingosine, and phosphatidic acid. Calcium, sodium, potassium, and magnesium ions after translocation through ion channels or by transport proteins can cause activation of release processes, contractile proteins, adenylate and guanylate cyclase, phosphodiesterases, protein kinases, phospholipases, ATPases and other enzymes. Modulatory interactions or "cross-talk" occurs both between the second messenger systems and the ion transport systems. Maitotoxin-from a marine dinoflagellate activates unique, calcium channels, which do not appear to be identical to any know calcium-channel, including the so-called calcium release-activated calcium (CRAC) channel. However, both maitotoxin and CRAC channels are effectively blocked by certain imidazoles (SKF 96365, miconazole, clotrimazole). Both channels are also blocked by trifluoperazine, but there are many other agents that block only the maitotoxin-activated channel. Loperamide is one of the most potent blockers of maitotoxin-elicited channels, but causes an apparent enhancement of calcium influx through the CRAC-channels that have been opened as a result of receptor-, thapsigargin-, or ionomycin-elicited depletion of IP3-sensitive intracellular pools of calcium in a variety of cell types. The effect of loperamide is unique, highly dependent on structure, and not readily reversed by imidazoles. Loperamide does not have any effect on levels of intracellular calcium if CRAC channels have not been activated. Loperamide does not augment sphingosine-elicited influx of calcium. Thus, loperamide does not augment sphingosine-elicited influx of calcium nor does augment influx of calcium through L-type calcium channels. The imidazoles, in addition to blocking CRAC channels, cause both release and influx of calcium in HL60 cells. Calmidazolium causes the greatest influx, but simpler analogs of calmidazolium have no effect. Erythrina alkaloids cause both competitive and noncompetitive blockade of nicotinic channels. Erysovine is the most potent member of these alkaloids at the central neuronal nicotinic receptor-channel. Tropane analogs of epiboxidine had nanomolar affinities for central nicotinic receptor-channels. Remarkably an N-benzyl derivative retained agonist activity. From a series of tropanes related in structure to a Chinese herbal alkaloid baogongteng A, the analog 6beta-acetoxytropane proved to be a potent muscarinic agonist with some selectivity towards M2-receptors. Other analogs appeared to be selective towards M1-receptors and, therefore, may have potential in decreasing cognitive deficits.