Carbonic anhydrase IV and XIV knockout mice: Roles of the respective carbonic anhydrases in buffering the extracellular space in brain
Carbonic anhydrase IV and XIV knockout mice: Roles of the respective carbonic anhydrases in buffering the extracellular space in brain
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DOI：
10.1073/pnas.0508449102
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发表时间：
2005-11-15
影响因子：
11.1
通讯作者：
Sly, WS
中科院分区：
文献类型：
--
作者：
Shah, GN;Ulmasov, B;Sly, WS
先前的研究表明，细胞外碳酸酐酶（CA）在缓冲碱性pH值的变化，伴随着在大鼠和小鼠海马神经元的活动。CA IV和XIV都被提出来介导这种细胞外缓冲。为了研究这两种同工酶在归因于细胞外CA的这一和其他生理功能中的相对重要性，我们通过靶向诱变产生了CA IV和CA XIV敲除（KO）小鼠，并通过交叉单个无效小鼠产生了双重缺陷的CA IV/XIV KO小鼠。虽然CA IV和CA XIV无效小鼠都是可行的，CA IV无效产生的数量比预测的要少，表明胎儿或出生后损失，这优先影响女性。CA IV/XIV双KO小鼠的产量也低于预测值，且小于WT小鼠，许多雌性小鼠在断奶前后过早死亡。对这些KO小鼠海马切片的电生理学研究表明，在没有另一种CA的情况下，任一种CA都可以介导海马切片中突触传递后的缓冲，但是消除两者几乎与CA抑制剂苯甲酰胺在阻断WT小鼠中观察到的缓冲方面一样有效。因此，CA IV和CA XIV都有助于中枢神经系统中的细胞外缓冲，尽管CA IV在海马中似乎更重要。这些单独的和双KO小鼠应该是有价值的工具，在澄清每个CA的相对贡献，其他生理功能的细胞外CA已牵连。
Previous studies have implicated extracellular carbonic anhydrases (CAs) in buffering the alkaline pH shifts that accompany neuronal activity in the rat and mouse hippocampus. CAs IV and XIV both have been proposed to mediate this extracellular buffering. To examine the relative importance of these two isozymes in this and other physiological functions attributed to extracellular CAs, we produced CA IV and CA XIV knockout (KO) mice by targeted mutagenesis and the doubly deficient CA IV/XIV KO mice by intercrossing the individual null mice. Although CA IV and CA XIV null mice both are viable, the CA IV nulls are produced in smaller numbers than predicted, indicating either fetal or postnatal losses, which preferentially affect females. CA IV/XIV double KO mice are also produced in fewer numbers than predicted and are smaller than WT mice, and many females die prematurely before and after weaning. Electrophysiological studies on hippocampal slices on these KO mice showed that either CA can mediate buffering after synaptic transmission in hippocampal slices in the absence of the other, but that eliminating both is nearly as effective as the CA inhibitor, benzolamide, in blocking the buffering seen in the WT mice. Thus, both CA IV and CA XIV contribute to extracellular buffering in the central nervous system, although CA IV appears to be more important in the hippocampus. These individual and double KO mice should be valuable tools in clarifying the relative contributions of each CA to other physiological functions where extracellular CAs have been implicated.