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首页> 外文期刊>American Journal of Physiology >Apparent receptor-mediated activation of Ca2+-dependent conductive Cl- transport by shark-derived polyaminosterols.
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Apparent receptor-mediated activation of Ca2+-dependent conductive Cl- transport by shark-derived polyaminosterols.

机译：鲨鱼衍生的聚氨基甾醇对受体介导的Ca2 +依赖性传导性Cl-转运的活化作用。

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The shark liver antimicrobial polyaminosterol squalamine is an angiogenesis inhibitor under clinical investigation as an anti-cancer agent and as a treatment for the choroidal neovascularization associated with macular degeneration of the retina. The related polyaminosterol MSI-1436 is an appetite suppressant that decreases systemic insulin resistance. However, the mechanisms of action of these polyaminosterols are unknown. We report effects of MSI-1436 on Xenopus oocytes consistent with the existence of a receptor for polyaminosterols. MSI-1436 activates bidirectional, trans-chloride-independent Cl- flux in Xenopus oocytes. At least part of this DIDS-sensitive Cl- flux is conductive, as measured using two-electrode voltage-clamp and on-cell patch-clamp techniques. MSI-1436 also elevates cytosolic Ca2+ concentration ([Ca2+]) and increases bidirectional 45Ca2+ flux. Activation of Cl- flux and elevation of cytosolic [Ca2+] by MSI-1436 both are accelerated by lowering bath Ca2+ and are not acutely inhibited by extracellular EGTA. Elevation of cytosolic [Ca2+] by MSI-1436 requires heparin-sensitive intracellular Ca2+ stores. Although injected EGTA abolishes the increased conductive Cl- flux, that Cl- flux is not dependent on heparin-sensitive stores. In low-bath Ca2+ conditions, several structurally related polyaminosterols act as strong agonists or weak agonists of conductive Cl- flux in oocytes. Weak agonist polyaminosterols antagonize the strong agonist, MSI-1436, but upon addition of the conductive Cl- transport inhibitor DIDS, they are converted into strong agonists. Together, these properties operationally define a polyaminosterol receptor at or near the surface of the Xenopus oocyte, provide an initial description of receptor signaling, and suggest routes toward further understanding of a novel class of appetite suppressants and angiogenesis inhibitors.
机译：鲨鱼肝抗菌素聚氨基固醇角鲨胺是一种血管生成抑制剂，在临床研究中作为抗癌剂和与视网膜黄斑变性相关的脉络膜新生血管形成的治疗剂。相关的聚氨基固醇MSI-1436是一种食欲抑制剂，可降低全身胰岛素抵抗。但是，这些聚氨基甾醇的作用机理尚不清楚。我们报告MSI-1436对爪蟾卵母细胞与聚氨基甾醇受体的存在一致的影响。 MSI-1436激活非洲爪蟾卵母细胞中双向，不依赖于氯化物的Cl-通量。用双电极电压钳位和单元上的膜片钳位技术测量，这种对DIDS敏感的Cl-通量的至少一部分是导电的。 MSI-1436还可以提高胞质Ca2 +浓度（[Ca2 +]）并增加双向45Ca2 +通量。 MSI-1436的Cl-通量活化和胞质[Ca2 +]的升高均通过降低浴液Ca2 +来加速，并且不受细胞外EGTA的急性抑制。 MSI-1436使胞质[Ca2 +]升高需要肝素敏感的细胞内Ca2 +存储。尽管注入的EGTA消除了增加的传导性Cl-通量，但该Cl-通量不依赖于肝素敏感的药物。在低浴Ca2 +条件下，几种结构相关的聚氨基甾醇在卵母细胞中充当导电性Cl-通量的强激动剂或弱激动剂。弱激动剂聚氨基甾醇拮抗强激动剂MSI-1436，但在添加导电的Cl转运抑制剂DIDS后，它们会转化为强激动剂。在一起，这些性质可操作地在爪蟾卵母细胞表面或附近定义了聚氨基甾醇受体，提供了受体信号传导的初步描述，并提出了进一步了解新型食欲抑制剂和血管生成抑制剂的途径。

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