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

锌是蛋白质的重要组成部分，估计占人类基因组的3%到10%。令人惊讶的是，我们对其胞质浓度的调节知之甚少。两个蛋白家族与锌转运有关——ZnT蛋白家族降低胞浆内锌浓度，而Zip蛋白家族促进锌从细胞外空间或从囊泡到胞浆的转运。在ZnT蛋白中，ZnT-1和ZnT-10是唯一存在于质膜上的转运蛋白，但尚未进行研究。ZnT-1被设想为将锌从细胞质转运到细胞外空间。然而，关于交换功能的证据很少，也很贫乏。此外，反离子和输运所需的能量来源都没有被确定。最近的证据表明，ZnT-1在含有高压活化钙通道的细胞中广泛表达。ZnT-1影响心脏、PC12、HEK293、POGRS1颗粒细胞和爪蟾卵母细胞中的l型钙电流。相互作用的机制尚不清楚，可能取决于Cav β亚基和ZnT-1之间的相互作用。常规灭活小鼠ZnT-1基因Slca1可导致胚胎致死。我们已经构建了一个条件Cre-lox为基础的载体，它将允许组织特异性缺失Slca1基因，以产生在心脏或大脑中缺乏ZnT-1蛋白的小鼠。

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.