Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization
Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization
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DOI：
10.1523/jneurosci.1689-07.2007
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发表时间：
2007-11-07
影响因子：
5.3
通讯作者：
Straub, Richard E.
中科院分区：
文献类型：
--
作者：
Iizuka, Yukihiko;Sei, Yoshitatsu;Straub, Richard E.
精神分裂症易感基因抗strobrevin-binding protein 1 （DTNBP1）编码异常结合蛋白（dysbindin），异常结合蛋白及其结合伙伴是溶酶体相关细胞器复合物1 （bloc1）生物发生的重要组成部分。Dysbindin的表达在精神分裂症脑组织中减少，但其导致发病机制和症状的分子机制尚不清楚。我们研究了转染DTNBP1 siRNA对人SH-SY5Y神经母细胞瘤细胞和大鼠原代皮质神经元细胞表面多巴胺D-2受体（DRD2）水平的影响。DTNBP1 siRNA降低异常结合蛋白，增加细胞表面DRD2，阻断多巴胺诱导的DRD2内化。沉默的siRNA产生了类似的效果。相反，dysbindin的减少并没有改变多巴胺D-1。受体（DRD1）水平，或其基础或多巴胺诱导的内化。DRD2激动剂喹匹罗降低了异常结合蛋白下调细胞中CREB （cAMP反应元件结合蛋白）的磷酸化，证明了DRD2上调引起的细胞内信号传导增强。这是首次证明精神分裂症易感基因对DRD2信号通路发挥功能作用，而DRD2信号通路长期以来一直被认为与精神分裂症有关。我们提出了一种分子机制，其中DTNBP1的风险等位基因，或其他下调结合异常的因素，损害了block -1运输DRD2的能力，但对DRD1的运输几乎没有影响。受损的DRD2运输减少了多巴胺诱导的内化，并且随着更多的受体保留在细胞表面，多巴胺刺激产生过量的细胞内信号。这种相对于DRD1的DRD2信号的增加可能导致精神分裂症特征的多巴胺能神经传递失衡。
The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D-2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D-1. receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.