Lee Seol-Ae, Suh Yeongjun, Lee Saebom, Jeong Jaehoon, Kim Soo Jeong, Kim So Jung, Park Sang Ki
Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea.
Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea
FASEB J. 2017 Jun;31(6):2301-2313. doi: 10.1096/fj.201600755RR. Epub 2017 Feb 21.
The dopaminergic system plays an essential role in various functions of the brain, including locomotion, memory, and reward, and the deregulation of dopaminergic signaling as a result of altered functionality of dopamine D2 receptor (DRD2) is implicated in multiple neurologic and psychiatric disorders. Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Here, we tested the hypothesis that TSPAN7 may be a binding partner of DRD2 that is involved in the regulation of its functional activity. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization. Immunocytochemical analysis revealed that TSPAN7 that resides in the plasma membrane and early and late endosomes promoted internalization of DRD2 and its localization to endosomal compartments of the endocytic pathway. Furthermore, we observed that TSPAN7 deficiency increased surface localization of DRD2 concurrent with the decrease of its endocytosis, regardless of dopamine treatment. Finally, TSPAN7 negatively affects DRD2-mediated signaling. These results disclosed a previously uncharacterized role of TSPAN7 in the regulation of the expression and functional activity of DRD2 by postendocytic trafficking.-Lee, S.-A., Suh, Y., Lee, S., Jeong, J., Kim, S. J., Kim, S. J., Park, S. K. Functional expression of dopamine D2 receptor is regulated by tetraspanin 7-mediated postendocytic trafficking.
多巴胺能系统在大脑的各种功能中起着至关重要的作用，包括运动、记忆和奖赏，而多巴胺D2受体（DRD2）功能改变导致的多巴胺能信号失调与多种神经和精神疾病有关。四跨膜蛋白-7（TSPAN7）在不同组织中表达程度不同，在大脑中表达水平最高，TSPAN7的多个突变与智力残疾有关。在此，我们检验了一个假设，即TSPAN7可能是DRD2的结合伴侣，参与其功能活性的调节。我们的结果表明，TSPAN7与DRD2相关，并通过增强DRD2的内化作用降低其表面表达。免疫细胞化学分析显示，位于质膜以及早期和晚期内体中的TSPAN7促进了DRD2的内化及其在内吞途径内体区室的定位。此外，我们观察到，无论是否用多巴胺处理，TSPAN7缺乏都会增加DRD2的表面定位，同时其胞吞作用降低。最后，TSPAN7对DRD2介导的信号传导有负面影响。这些结果揭示了TSPAN7在通过内吞后运输调节DRD2的表达和功能活性方面以前未被描述的作用。-李，S.-A.，苏，Y.，李，S.，郑，J.，金，S.J.，金，S.J.，朴，S.K. 多巴胺D2受体的功能表达受四跨膜蛋白7介导的内吞后运输调节。
