Luderman Kathryn D, Chen Rong, Ferris Mark J, Jones Sara R, Gnegy Margaret E
Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5632, USA.
Neuropharmacology. 2015 Feb;89:335-41. doi: 10.1016/j.neuropharm.2014.10.012.
The focus of this study was the regulation of the D2-like dopamine autoreceptor (D2 autoreceptor) by protein kinase Cβ, a member of the protein kinase C (PKC) family. Together with the dopamine transporter, the D2 autoreceptor regulates the level of extracellular dopamine and thus dopaminergic signaling. PKC regulates neuronal signaling via several mechanisms, including desensitizing autoreceptors to increase the release of several different neurotransmitters. Here, using both PKCβ(-/-) mice and specific PKCβ inhibitors, we demonstrated that a lack of PKCβ activity enhanced the D2 autoreceptor-stimulated decrease in dopamine release following both chemical and electrical stimulations. Inhibition of PKCβ increased surface localization of D2R in mouse striatal synaptosomes, which could underlie the greater sensitivity to quinpirole following inhibition of PKCβ. PKCβ(-/-) mice displayed greater sensitivity to the quinpirole-induced suppression of locomotor activity, demonstrating that the regulation of the D2 autoreceptor by PKCβ is physiologically significant. Overall, we have found that PKCβ downregulates the D2 autoreceptor, providing an additional layer of regulation for dopaminergic signaling. We propose that in the absence of PKCβ activity, surface D2 autoreceptor localization and thus D2 autoreceptor signaling is increased, leading to less dopamine in the extracellular space and attenuated dopaminergic signaling.
本研究的重点是蛋白激酶C（PKC）家族成员蛋白激酶Cβ对D2样多巴胺自身受体（D2自身受体）的调节作用。D2自身受体与多巴胺转运体一起调节细胞外多巴胺水平，从而调节多巴胺能信号传导。PKC通过多种机制调节神经元信号传导，包括使自身受体脱敏以增加几种不同神经递质的释放。在这里，我们使用PKCβ基因敲除小鼠和特异性PKCβ抑制剂，证明缺乏PKCβ活性会增强化学和电刺激后D2自身受体刺激引起的多巴胺释放减少。抑制PKCβ会增加小鼠纹状体突触体中D2R的表面定位，这可能是PKCβ抑制后对喹吡罗敏感性增加的基础。PKCβ基因敲除小鼠对喹吡罗诱导的运动活动抑制表现出更高的敏感性，表明PKCβ对D2自身受体的调节在生理上具有重要意义。总体而言，我们发现PKCβ下调D2自身受体，为多巴胺能信号传导提供了额外的调节层次。我们提出，在缺乏PKCβ活性的情况下，表面D2自身受体的定位以及因此D2自身受体信号传导会增加，导致细胞外空间多巴胺减少，多巴胺能信号传导减弱。
