Molecular Mechanisms of Cellular Stress and Inflammation Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Int J Mol Sci. 2022 Feb 10;23(4):1974. doi: 10.3390/ijms23041974.
Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity.
滥用药物会导致局部和全身体温过高，这是内质网 (ER) 应激和未折叠蛋白反应 (UPR) 的已知触发因素。内质网应激和 UPR 的另一个触发因素是内质网钙耗竭，这会导致内质网排出，即内质网驻留蛋白的分泌。在啮齿动物模型中，致幻剂如 3,4-亚甲基二氧甲基苯丙胺 (MDMA，“摇头丸”) 会在大脑中产生体温过高的情况，并导致毒性，这种毒性会受到环境温度和其他药物（如咖啡因）的影响。在人体研究中，MDMA 刺激了核心体温的急性、剂量依赖性增加，但 MDMA 和咖啡因联合使用的研究仍然是临床研究的一个课题。在这里，我们在过热细胞模型中检查了 MDMA 和咖啡因联合暴露下内质网驻留蛋白的分泌和 UPR 的激活。我们表明，过热会触发正常内质网驻留蛋白的分泌，而 MDMA、咖啡因或这两种药物的组合会增强这种异常的蛋白分泌。过热会激活 UPR，但添加 MDMA 或咖啡因不会改变经典的 UPR 基因表达，尽管这些药物会影响 UPR 相关蛋白的内质网排出。一个例外是在暴露于过热条件下接受 MDMA 治疗的细胞中增加了 XBP1 mRNA 水平。这些发现表明，在过热条件下使用摇头丸会加剧内质网蛋白质稳态的破坏，导致细胞毒性。
