Funktionsanalyse des Zinktransporters I (ZnT-1) mittels genetischer Deletion

使用基因删除对锌转运蛋白 I (ZnT-1) 进行功能分析

• 批准号: 67028454
• 负责人: Professor Dr. Franz Hofmann
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/67028454?language=en
• 关键词: Funktionsanalyse; des; Zinktransporters; ZnT; mittels

Zinc is an essential part of proteins estimated to compromise 3 % to 10 % of the human genome. Surprisingly little is known on the regulation of its cytosolic concentrations. Two protein families have been implicated in zinc transport- The ZnT family lowers cytosolic zinc concentrations, whereas the Zip protein family promotes the transport of zinc from the extracellular space or from vesicles to the cytosol. Among the ZnT proteins, ZnT-1 and ZnT-10, that were not studied at all, are the only transporter present at the plasma membrane. ZnT-1 has been envisioned to transport zinc from the cytosol to the extracellular space. However, the evidence for the exchange function are scarce and poor. In addition, neither the counter ion nor the energy source necessary for the transport has been identified. Recent evidence suggests that ZnT-1 is widely expressed in cells that contain the high voltage activated calcium channels. ZnT-1 affects L-type calcium currents in heart, PC12, HEK293, POGRS1 granulosa cells and Xenopus oocytes. The mechanism of interaction is unclear and may depend on an interaction between the Cav β subunit and ZnT-1. Conventional inactivation of the murine ZnT-1 gene Slca1 results in embryonic lethality. We have constructed a conditional Cre-lox based vector that will allow tissue specific deletion of the Slca1 gene to generate mice that lack the ZnT-1 protein either in the heart or the brain.

锌是蛋白质的重要组成部分，据估计，这些蛋白质占人类基因组的3%到10%。令人惊讶的是，人们对其胞浆浓度的调节知之甚少。有两个蛋白质家族参与了锌的转运--ZNT家族降低胞内锌浓度，而Zip蛋白家族促进锌从细胞外空间或小泡到胞浆的转运。在ZNT蛋白中，ZNT-1和ZNT-10是唯一存在于质膜上的转运蛋白。ZNT-1被设想为将锌从胞浆运输到细胞外空间。然而，交换功能的证据既稀少又贫乏。此外，既没有确定反离子，也没有确定运输所需的能源。最近的证据表明，ZNT-1在含有高电压激活的钙通道的细胞中广泛表达。ZNT-1影响心脏、PC12、HEK293、POGRS1颗粒细胞和非洲爪哇卵母细胞的L钙电流。这种相互作用的机制尚不清楚，可能依赖于Cavβ亚基和ZnT-1之间的相互作用。小鼠ZNT-1基因SLca1的常规失活会导致胚胎死亡。我们已经构建了一个基于条件Cre-lox的载体，它将允许SLca1基因的组织特异性缺失，从而产生心脏或大脑中缺乏ZNT-1蛋白的小鼠。