Activation of ATP-sensitive K+ (KATP) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release
Activation of ATP-sensitive K+ (KATP) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release
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DOI：
10.1073/pnas.1834314100
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发表时间：
2003-09-30
影响因子：
11.1
通讯作者：
Rice, ME
中科院分区：
文献类型：
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作者：
Avshalumov, MV;Rice, ME
在许多细胞中，atp敏感的K+通道（K- atp通道）将代谢状态与兴奋性结合起来。例如，在胰腺细胞中，这种耦合调节胰岛素的释放。虽然K-ATP通道在大脑中大量表达，但它们的生理作用和调节它们的因素却知之甚少。我们之前报道过纹状体中多巴胺（DA）的释放受内源性H2O2的调节，H2O2是由谷氨酸α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体激活下游产生的。本文研究了对h2o2敏感的K-ATP通道是否参与谷氨酸和γ -氨基丁酸（GABA）对da释放的调节。这个问题很重要，因为da -谷氨酸相互作用是大脑功能的基础，包括运动控制和认知。采用局部电刺激豚鼠纹状体切片诱发突触DA释放，并采用碳纤维微电极和快速扫描循环伏安法实时监测。k - atp通道拮抗剂格列本脲消除了GYKI-52466[1-（4-氨基苯基）-4-甲基-7,8-亚甲二氧基- 5h -2,3-苯二氮卓盐酸]阻断ampa受体时通常出现的h2o2依赖性DA释放增加，以及微毒素阻断gaba型a受体时出现的DA释放减少。相比之下，线粒体K- atp通道阻滞剂5-羟基癸酸酯无效，d -2受体拮抗剂舒匹利和G蛋白偶联K+通道抑制剂特拉平也无效。磺酰脲受体1 （SUR1）选择性k - atp通道开启剂Diazoxide可以阻止H2O2、谷氨酸和GABA对DA的调节，而sur2选择性开启剂cromakalim则没有作用。因此，内源性H2O2激活质膜中含有sur1的K-ATP通道，抑制DA的释放。这些数据不仅表明K-ATP通道可以调节快速突触传递时CNS递质释放，而且还可以引入H2O2作为K-ATP通道调节剂。
In many cells, ATP-sensitive K+ channels (K-ATP channels) couple metabolic state to excitability. In pancreatic beta cells, for example, this coupling regulates insulin release. Although K-ATP channels are abundantly expressed in the brain, their physiological role and the factors that regulate them are poorly understood. One potential regulator is H2O2, We reported previously that dopamine (DA) release in the striatum is modulated by endogenous H2O2, generated downstream from glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor activation. Here we investigated whether H2O2-sensitive K-ATP channels contribute to DA-release modulation by glutamate and gamma-aminobutyric acid (GABA). This question is important because DA-glutamate interactions underlie brain functions, including motor control and cognition. Synaptic DA release was evoked by using local electrical stimulation in slices of guinea pig striatum and monitored in real time with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. The K-ATP-channel antagonist glibenclamide abolished the H2O2-dependent increase in DA release usually seen with AMPA-receptor blockade by GYKI-52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] and the decrease in DA release seen with GABA-type-A-receptor blockade by picrotoxin. In contrast, 5-hydroxydecanoate, a mitochondrial K-ATP-channel blocker, was ineffective, as were sulpiride, a D-2-receptor antagonist, and tertiapin, a G protein-coupled K+-channel inhibitor. Diazoxide, a sulfonylurea receptor 1 (SUR1)-selective K-ATP-channel opener, prevented DA modulation by H2O2, glutamate, and GABA, whereas cromakalim, a SUR2-selective opener, did not. Thus, endogenous H2O2 activates SUR1-containing K-ATP channels in the plasma membrane to inhibit DA release. These data not only demonstrate that K-ATP channels can modulate CNS transmitter release in response to fast-synaptic transmission but also introduce H2O2 as a K-ATP-channel regulator.