Single KATP channel opening in response to stimulation of AMPA/kainate receptors is mediated by Na+ accumulation and submembrane ATP and ADP changes
Single KATP channel opening in response to stimulation of AMPA/kainate receptors is mediated by Na+ accumulation and submembrane ATP and ADP changes
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DOI：
10.1113/jphysiol.2012.248369
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发表时间：
2013-05-01
影响因子：
5.5
通讯作者：
Mironov, S. L.
中科院分区：
文献类型：
--
作者：
Mollajew, R.;Toloe, J.;Mironov, S. L.
关键点中心点KATP通道可以抑制激活谷氨酸能受体（GluRs）后CNS神经元的过度兴奋，我们在脑干和海马神经元中检测了这种功能性相互作用。中心点GluR刺激可增加KATP单通道的活性，而这种活性不受细胞内钙、活性氧和渗透压的影响，在抑制钠离子内流后被消除。中心点ATP和钠成像表明GluRs和KATP通道之间的功能性串扰是由Na +-K +-ATP酶介导的。在功能完整的脑干切片中，中心点GluR在缺氧期间促进KATP通道开放，在海马切片中促进海马样活动。中心点我们认为神经元活动消耗膜下ATP，增加ADP水平，促进KATP通道开放，抑制谷氨酸引起的不受控制的兴奋。过度刺激谷氨酸能受体（GluRs）可使神经元过度兴奋。这可以通过连接代谢和神经元活动的KATP通道来抑制，但尚未在单通道水平上检查串扰。在脑干和海马神经元中，GluR激动剂增加KATP通道开放概率（Popen）的相对效应：红藻氨酸近似于AMPA> NMDA> t-ACPD。抑制钙内流和螯合细胞内钙没有修改的影响。红藻氨酸盐没有增加用roGFP 1测量的活性氧的产生。H_2O_2使Popen略有增加，但GluR的作用没有改变。GluR的作用在无Na+的溶液中和阻断Na +-K +-ATP酶后被消除。在开放细胞膜片钳测量KATP通道被ATP抑制，ADP刺激，红藻氨酸是有效的，只有在ATP的存在。GluR刺激增强ATP消耗，降低膜下ATP水平，而代谢中毒减少散装ATP。模型显示，强烈的ATP消耗和ADP积累附近的膜，这两种效应都有助于增加后，GluR刺激Popen。红藻氨酸和缺氧激活功能性脑干脑片的KATP通道。抑制有氧ATP产生和GluR刺激在缺氧时KATP通道开放中的效果大致相同。无镁溶液诱导海马脑片中的神经元样活性伴随着ATP减少和KATP通道开放。我们认为KATP通道和GluRs在功能上是耦合的，可以调节CNS神经元中神经元活动的长期变化。
Key points center dot KATP channels can suppress overexcitation of CNS neurons after activation of glutamatergic receptors (GluRs), and we examined this functional interaction in the brainstem and hippocampal neurons. center dot GluR stimulation increased the activity of single KATP channels that was not mediated by intracellular calcium, reactive oxygen species and osmotic stress, and was abolished after inhibition of sodium influx. center dot ATP and sodium imaging indicated that functional cross-talk between GluRs and KATP channels is mediated by Na+-K+-ATPase. center dot GluR contributed to KATP channel opening during hypoxia in functionally intact brainstem slices and seizure-like activity in the hippocampal slices. center dot We propose that neuronal activity depletes submembrane ATP, and increases ADP levels and promotes KATP channel opening that dampen uncontrolled excitation by glutamate. Abstract Excessive stimulation of glutamatergic receptors (GluRs) can overexcite neurons. This can be dampened by KATP channels linking metabolic and neuronal activities, but the cross-talk has not yet been examined on the single channel level. In the brainstem and hippocampal neurons, GluR agonists augmented the open state probability (Popen) of KATP channels with relative efficacy: kainate approximate to AMPA > NMDA > t-ACPD. Inhibition of calcium influx and chelation of intracellular calcium did not modify the effects. Kainate did not augment production of reactive oxygen species measured with roGFP1. H2O2 slightly increased Popen, but GluR effects were not modified. GluR actions were abolished in Na+-free solutions and after blockade of Na+-K+-ATPase. KATP channels in open-cell patch-clamp measurements were inhibited by ATP, stimulated by ADP, and kainate was effective only in the presence of ATP. GluR stimulation enhanced ATP consumption that decreased submembrane ATP levels, whereas metabolic poisoning diminished bulk ATP. Modelling showed strong ATP depletion and ADP accumulation near the membrane, and both effects contributed to Popen increases after GluR stimulation. Kainate and hypoxia activated KATP channels in the functional brainstem slices. Inhibition of aerobic ATP production and GluR stimulation were about equally effective in KATP channel opening during hypoxia. Induction of seizure-like activity in hippocampal slices with Mg2+-free solutions was accompanied by ATP decrease and KATP channel opening. We propose that KATP channels and GluRs are functionally coupled that can regulate long-lasting changes of neuronal activity in the CNS neurons.