Hentschke Moritz, Wiemann Martin, Hentschke Suna, Kurth Ingo, Hermans-Borgmeyer Irm, Seidenbecher Thomas, Jentsch Thomas J, Gal Andreas, Hübner Christian A
Department of Human Genetics, UKE-Hamburg, Butenfeld 42, 22529 Hamburg, Germany.
Mol Cell Biol. 2006 Jan;26(1):182-91. doi: 10.1128/MCB.26.1.182-191.2006.
Neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH. The sodium-independent electroneutral anion exchangers (AEs) exchange intracellular bicarbonate for extracellular chloride and thereby lower the intracellular pH. Recently, a significant association was found with the variant Ala867Asp of the anion exchanger AE3, which is predominantly expressed in brain and heart, in a large cohort of patients with idiopathic generalized epilepsy. To analyze a possible involvement of AE3 dysfunction in the pathogenesis of seizures, we generated an AE3-knockout mouse model by targeted disruption of Slc4a3. AE3-knockout mice were apparently healthy, and neither displayed gross histological and behavioral abnormalities nor spontaneous seizures or spike wave complexes in electrocorticograms. However, the seizure threshold of AE3-knockout mice exposed to bicuculline, pentylenetetrazole, or pilocarpine was reduced, and seizure-induced mortality was significantly increased compared to wild-type littermates. In the pyramidal cell layer of the hippocampal CA3 region, where AE3 is strongly expressed, disruption of AE3 abolished sodium-independent chloride-bicarbonate exchange. These findings strongly support the hypothesis that AE3 modulates seizure susceptibility and, therefore, are of significance for understanding the role of intracellular pH in epilepsy.
神经元活动会导致神经元、神经胶质细胞和细胞外间隙出现显著的pH值变化。多种转运机制参与细胞外和细胞内pH值的微调与调节。钠非依赖型电中性阴离子交换体（AEs）将细胞内碳酸氢根与细胞外氯离子进行交换，从而降低细胞内pH值。最近，在一大群特发性全身性癫痫患者中发现，主要在脑和心脏中表达的阴离子交换体AE3的Ala867Asp变体存在显著关联。为了分析AE3功能障碍在癫痫发作发病机制中可能的作用，我们通过靶向破坏Slc4a3生成了AE3基因敲除小鼠模型。AE3基因敲除小鼠看起来健康，既未表现出明显的组织学和行为异常，也未出现自发癫痫发作或脑电图中的棘波复合波。然而，与野生型同窝小鼠相比，暴露于荷包牡丹碱、戊四氮或毛果芸香碱的AE3基因敲除小鼠的癫痫发作阈值降低，且癫痫发作诱导的死亡率显著增加。在AE3强烈表达的海马CA3区锥体细胞层，AE3的破坏消除了钠非依赖型氯-碳酸氢根交换。这些发现有力地支持了AE3调节癫痫易感性的假说，因此对于理解细胞内pH值在癫痫中的作用具有重要意义。
