5-HT 受体介导电联蛋白 δ 的磷酸化对于 p-氯苯丙胺诱导的小鼠 5-羟色胺能损伤至关重要。
5-HT receptor-mediated PKCδ phosphorylation is critical for serotonergic impairments induced by p-chloroamphetamine in mice.
机构信息
Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea; School of Medicine and Pharmacy - Hoa Quy Ward, The University of Da Nang, Da Nang 550000, Viet Nam.
Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
出版信息
Food Chem Toxicol. 2020 Jul;141:111395. doi: 10.1016/j.fct.2020.111395. Epub 2020 May 11.
p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT receptor gene expression, but significantly increased 5-HT receptor gene expression. Furthermore, 5-HT receptor antagonist MDL11939, but not 5-HT receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT receptor-mediated serotonergic effects. Our results suggest that 5-HT receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ.
对氯苯丙胺（PCA），一种苯丙胺衍生物，已被证明会导致 5-羟色胺能毒性。然而，PCA 引起的 5-羟色胺能毒性的确切机制仍不清楚。在这项研究中，PCA 处理（20mg/kg，ip）并未显著改变 5-羟色胺受体基因表达，但显著增加了 5-羟色胺受体基因表达。此外，5-羟色胺受体拮抗剂 MDL11939，但不是 5-羟色胺受体拮抗剂 WAY100635，显著减轻了 PCA 诱导的 5-羟色胺能损伤。我们研究了 PCA 是否激活了一种特定的蛋白激酶 C（PKC）同工型，因为先前的证据表明 PKC 参与了安非他命诱导的神经毒性。我们观察到 PCA 处理显著增加了 PKCδ 在所有 PKC 同工型中的表达水平。MDL11939 处理显著减轻了 PCA 诱导的 PKCδ 磷酸化。然而，在小鼠中，MDL11939 处理并未改变 PCA 诱导的 5-羟色胺受体基因表达的增加，这表明 5-羟色胺受体是 PKCδ 激活的上游分子。罗特林（PKCδ 的药理学抑制剂）或 PKCδ 敲除显著减轻了 5-羟色胺能行为。然而，MDL11939 对 PKCδ 敲除引起的衰减没有显示出任何额外的作用，这表明 PKCδ 基因是 5-羟色胺受体介导的 5-羟色胺能作用的分子靶点。我们的结果表明，5-羟色胺受体通过激活 PKCδ 介导 PCA 诱导的 5-羟色胺能损伤。
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