Caffeine and MDMA (ecstasy) exacerbate ER stress triggered by hyperthermia

Hyperthermia—elevated body temperature—triggers the abnormal secretion of proteins normally retained inside the endoplasmic reticulum (ER), a process called ER exodosis. The club drugs MDMA (ecstasy) and caffeine, alone or combined, worsen this protein leakage in a cellular model. Hyperthermia also activates the unfolded protein response (UPR), a cellular stress pathway, but the drugs do not alter most UPR-related gene expression despite increasing ER exodosis of UPR proteins. One exception: MDMA raised BiP/Grp78 mRNA levels under hyperthermia. These results suggest that using club drugs in hot environments disrupts ER protein balance, potentially increasing cell toxicity.

Study at a glance

Abstract

Abstract 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. 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. 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 canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/Grp78 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. Highlights ER resident proteins are redistributed into the extracellular space in response to hyperthermia and caffeine and MDMA further enhance this secretion. Stabilizing ER calcium and overexpressing KDEL receptors reduces ER resident protein secretion following hyperthermia. Hyperthermia triggers a UPR response with MDMA augmenting BiP expression in hyperthermic conditions.