D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels.
D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels.
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DOI：
10.1152/jn.00998.2007
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发表时间：
2008-02
影响因子：
2.5
通讯作者：
S. Ramanathan;T. Tkatch;J. Atherton;Charles J. Wilson;M. Bevan
中科院分区：
文献类型：
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作者：
S. Ramanathan;T. Tkatch;J. Atherton;Charles J. Wilson;M. Bevan
丘脑下核（STN）神经元的活动模式与运动功能/功能障碍密切相关，并由帕金森病（PD）中退行性多巴胺能神经元直接调节。为了了解多巴胺和多巴胺消耗如何影响STN的活性，我们使用膜片钳记录技术研究了d2样多巴胺受体的功能/信号通路/底物。在大鼠脑切片中，d2样多巴胺受体激活去极化STN神经元，增加其自主活动的频率/不规则性，线性化/增强其放电响应于电流注射。急性分离神经元中d2样受体的激活减少了阈上电压阶跃引起的瞬态外向电流。调节被d2样受体拮抗剂抑制，并被电压依赖性Ca2+ (Cav)通道或小电导Ca2+依赖性K+ (SKCa)通道阻滞剂或无Ca2+介质阻断。由于Cav通道是G（i/o）连接受体的靶标，因此研究了步进和动作电位波形诱发的Cav通道电流的作用。d2样受体的激活降低了Cav2.2通道的电导，但没有降低Cav1通道的电导。调制部分是由γ γ γ亚基的直接结合介导的，因为它被短暂的去极化减弱。D2和/或D3多巴胺受体可能介导调节，因为D4选择性激动剂无效，并且可以检测到编码D2和D3而非D4多巴胺受体的mRNA。脑切片记录证实，超极化后SKCa通道介导的动作电位被d2样多巴胺受体激活减弱。综上所述，这些数据表明d2样多巴胺受体可以有效地调节STN神经元Cav2.2和SKCa通道的功能偶联介导的放电负反馈控制。
The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D2-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D2-like receptor antagonist and occluded by voltage-dependent Ca2+ (Cav) channel or small-conductance Ca2+-dependent K+ (SKCa) channel blockers or Ca2+-free media. Because Cav channels are targets of G(i/o)-linked receptors, actions on step- and action potential waveform-evoked Cav channel currents were studied. D2-like receptor activation reduced the conductance of Cav2.2 but not Cav1 channels. Modulation was mediated, in part, by direct binding of Gbetagamma subunits because it was attenuated by brief depolarization. D2 and/or D3 dopamine receptors may mediate modulation because a D4-selective agonist was ineffective and mRNA encoding D2 and D3 but not D4 dopamine receptors was detectable. Brain slice recordings confirmed that SKCa channel-mediated action potential afterhyperpolarization was attenuated by D2-like dopamine receptor activation. Together, these data suggest that D2-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Cav2.2 and SKCa channels in STN neurons.