PDF(Pubmed)
Abstract：
SCH23390 is a widely used D1 dopamine receptor (D1R) antagonist that also elicits some D1R-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of 3H (+)-pentazocine to Sig1R. In this study, we investigated whether SCH23390 functions as an allosteric modulator of Sig1R. We detected increased Sig1R dissociation from binding immunoglobulin protein (BiP) and translocation of Sig1R to the plasma membrane in response to SCH23390 in transfected HEK293T and SH-SY5Y cells, respectively. Activation of Sig1R by SCH23390 was further confirmed by inhibition of GSK3β activity in a time- and dose-dependent manner; this effect was blocked by pretreatment with the Sig1R antagonist, BD1047, and by knockdown of Sig1R. SCH23390 also inhibited GSK3β in wild-type mice but not in Sig1R knockout mice. Finally, we showed that SCH23390 allosterically modulated the effect of the Sig1R agonist SKF10047 on inhibition of GSK3β. This positive allosteric effect of SCH23390 was further confirmed via promotion of neuronal protection afforded by SKF10047 in primary cortical neurons challenged with MPP+. These results provide the first evidence that SCH23390 elicits functional allosteric modulation of Sig1R. Our findings not only reveal novel pharmacological effects of SCH23390 but also indicate a potential mechanism for SCH23390-mediated D1R-independent effects. Therefore, attention should be paid to these Sig1R-mediated effects when explaining pharmacological responses to SCH23390.
摘要：
SCH23390是一种广泛使用的D1多巴胺受体（D1R）拮抗剂，也引起一些不依赖D1R的作用。我们之前发现苯并氮杂卓,SKF83959,SCH23390的类似物,产生Sigma-1受体(Sig1R)的正变构调节。SCH23390不结合Sig1R的邻位氧位点,但增强3H(+)-喷他佐辛与Sig1R的结合。在这项研究中,我们研究了SCH23390是否充当Sig1R的变构调节剂。我们在转染的HEK293T和SH-SY5Y细胞中检测到响应SCH23390的结合免疫球蛋白蛋白（BiP）和Sig1R易位到质膜的Sig1R解离增加，分别。通过以时间和剂量依赖性方式抑制GSK3β活性进一步证实了SCH23390对Sig1R的激活；这种作用被Sig1R拮抗剂预处理阻断，BD1047，并通过敲低Sig1R。SCH23390还在野生型小鼠中抑制GSK3β,但在Sig1R敲除小鼠中不抑制。最后,我们显示SCH23390变构调节Sig1R激动剂SKF10047对GSK3β的抑制作用。SCH23390的这种正变构效应通过促进SKF10047在用MPP+攻击的原代皮质神经元中提供的神经元保护而得到进一步证实。这些结果提供了SCH23390引发Sig1R的功能性变构调节的第一个证据。我们的发现不仅揭示了SCH23390的新药理作用，而且还表明了SCH23390介导的D1R非依赖性作用的潜在机制。因此,在解释对SCH23390的药理反应时，应注意这些Sig1R介导的作用。
