Na(+)/H(+) exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions.
Na(+)/H(+) exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions.
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DOI：
10.1111/j.1471-4159.2008.05355.x
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发表时间：
2008-07
影响因子：
4.7
通讯作者：
Sonsalla PK
中科院分区：
文献类型：
--
作者：
Rocha MA;Crockett DP;Wong LY;Richardson JR;Sonsalla PK
Na+/H+交换蛋白（NHE）参与细胞内pH和容量调节，并可能间接影响神经传递。丰富的NHE亚型1（NHE 1）也与代谢应激期间的脑细胞损伤有关。然而，在正常或代谢应激条件下，NHE 1或其他NHE亚型是否在纹状体多巴胺（DA）神经传递中发挥作用尚不清楚。我们的研究验证了以下假设：甲磺酸卡立泊来酯（HOE-642）抑制NHE可改变线粒体抑制剂丙二酸引起的小鼠纹状体DA溢出和DA能终末损伤。我们还探讨了NHE 1 -5在纹状体和黑质的表达。HOE-642的反向微透析引起短暂升高，随后DA溢出减少，伴随纹状体DA含量下降。HOE-642预处理减少了丙二酸盐诱导的DA溢出，但未降低代谢应激或后续DA能轴突损伤的强度。虽然NHE亚型1-5在纹状体和中脑中表达，但NHE 1蛋白并不共同位于黑质纹状体DA能神经元上。DA能神经元上不存在NHE 1共定位，表明HOE-642对纹状体DA溢出的影响是通过位于其他细胞类型上的NHE 1介导的，或者HOE-642通过多种NHE亚型起作用。
Na+/H+ exchanger (NHE) proteins are involved in intracellular pH and volume regulation and may indirectly influence neurotransmission. The abundant NHE isoform 1 (NHE1) has also been linked to brain cell damage during metabolic stress. It is not known, however, whether NHE1 or other NHE isoforms play a role in striatal dopamine (DA) neurotransmission under normal or metabolic stress conditions. Our study tested the hypothesis that NHE inhibition with cariporide mesilate (HOE-642) modifies striatal DA overflow and DAergic terminal damage in mice caused by the mitochondrial inhibitor malonate. We also explored the expression of NHE1–5 in the striatum and substantia nigra. Reverse microdialysis of HOE-642 elicited a transient elevation followed by a reduction in DA overflow accompanied by a decline in striatal DA content. HOE-642 pre-treatment diminished the malonate-induced DA overflow without reducing the intensity of the metabolic stress or subsequent DAergic axonal damage. Although NHE isoforms 1–5 are expressed in the striatum and midbrain, NHE1 protein was not co-located on nigrostriatal DAergic neurons. The absence of NHE1 co-location on DAergic neurons suggests that the effects of HOE-642 on striatal DA overflow are either mediated via NHE1 located on other cell types or that HOE-642 is acting through multiple NHE isoforms.
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影响因子：
4.2
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