Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block.
Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block.
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DOI：
10.1111/j.1460-9568.2012.08190.x
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Shepard PD
中科院分区：
文献类型：
--
作者：
Ji H;Tucker KR;Putzier I;Huertas MA;Horn JP;Canavier CC;Levitan ES;Shepard PD
中脑多巴胺神经元的爆发性活动反映了其内在起搏活动和突触输入之间的复杂相互作用。虽然负责在体内产生和调制的爆发的精确机制尚未建立，几个离子通道已经牵连的过程。以往的研究表明，非选择性阻断剂醚-一个-去-去相关基因（ERG）的K+通道是功能上的重要。在这里，电生理学与选择性化学和肽ERG通道阻滞剂（E-4031和rBeKm-1）和计算方法被用来定义的ERG通道的放电特性的中脑多巴胺神经元在体内和体外的贡献。选择性ERG通道阻断增加自发活动的频率以及对去极化电流脉冲的反应，而不改变尖峰频率适应。ERG通道阻滞也加速进入去极化失活引起的虚拟NMDA受体与动态钳的爆发，并显着延长持续去极化失活的持续时间，随后电刺激诱发的爆发。在体内，体细胞ERG阻滞与归因于双峰放电减少的爆发活性增加相关。总之，这些结果表明，多巴胺神经元ERG K+通道发挥了重要作用，限制兴奋性和最大限度地减少去极化失活。由于抗精神病药物的治疗作用与多巴胺神经元的去极化失活有关，并且心脏ERG通道的阻滞是这些药物的一个突出副作用，因此中枢神经系统中的ERG通道可能代表抗精神病药物开发的新靶点。
Bursting activity by midbrain dopamine neurons reflects the complex interplay between their intrinsic pacemaker activity and synaptic inputs. Although the precise mechanism responsible for the generation and modulation of bursting in vivo has yet to be established, several ion channels have been implicated in the process. Previous studies with nonselective blockers suggested that ether-a-go-go-related gene (ERG) K+ channels are functionally significant. Here, electrophysiology with selective chemical and peptide ERG channel blockers (E-4031 and rBeKm-1) and computational methods were used to define the contribution made by ERG channels to the firing properties of midbrain dopamine neurons in vivo and in vitro. Selective ERG channel blockade increased the frequency of spontaneous activity as well as the response to depolarizing current pulses without altering spike frequency adaptation. ERG channel block also accelerated entry into depolarization inactivation during bursts elicited by virtual NMDA receptors generated with the dynamic clamp, and significantly prolonged the duration of the sustained depolarization inactivation that followed pharmacologically evoked bursts. In vivo, somatic ERG blockade was associated with an increase in bursting activity attributed to a reduction in doublet firing. Taken together, these results show that dopamine neuron ERG K+ channels play a prominent role in limiting excitability and in minimizing depolarization inactivation. As the therapeutic actions of antipsychotic drugs are associated with depolarization inactivation of dopamine neurons and blockade of cardiac ERG channels is a prominent side effect of these drugs, ERG channels in the central nervous system may represent a novel target for antipsychotic drug development.
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影响因子：
2.9
作者：
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通讯作者：
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作者：
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通讯作者：
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