Abstract
N,N-dimethyltryptamine (DMT) is a potent endogenous hallucinogen present in the brain of humans and other mammals. Despite extensive research, its physiological role remains largely unknown. Recently, DMT has been found to activate the sigma-1 receptor (Sig-1R), an intracellular chaperone fulfilling an interface role between the endoplasmic reticulum (ER) and mitochondria. It ensures the correct transmission of ER stress into the nucleus resulting in the enhanced production of antistress and antioxidant proteins. Due to this function, the activation of Sig-1R can mitigate the outcome of hypoxia or oxidative stress. In this paper, we aimed to test the hypothesis that DMT plays a neuroprotective role in the brain by activating the Sig-1R. We tested whether DMT can mitigate hypoxic stress in in vitro cultured human cortical neurons (derived from induced pluripotent stem cells, iPSCs), monocyte-derived macrophages (moMACs), and dendritic cells (moDCs). Results showed that DMT robustly increases the survival of these cell types in severe hypoxia (0.5% O2) through the Sig-1R. Furthermore, this phenomenon is associated with the decreased expression and function of the alpha subunit of the hypoxia-inducible factor 1 (HIF-1) suggesting that DMT-mediated Sig-1R activation may alleviate hypoxia-induced cellular stress and increase survival in a HIF-1-independent manner. Our results reveal a novel and important role of DMT in human cellular physiology. We postulate that this compound may be endogenously generated in situations of stress, ameliorating the adverse effects of hypoxic/ischemic insult to the brain.
Highlights
Thought to be an opioid receptor, the sigma-1 receptor (Sig-1R) is classified as member of an orphan family after Su and colleagues had characterized the structural and biochemical features of the ligand binding site and identified the class as a non-opioid one (Su, 1982; Su et al, 1988)
Though the expression of Sig-1R has been demonstrated in human neural cell types, it has not been investigated in NSCs and in induced pluripotent stem cells (iPSCs)-derived cortical neurons
We found that 6 h of hypoxia treatment greatly induced the protein-level expression of hypoxia-inducible factor (HIF)-1α in human iPSC-derived neurons, monocyte-derived macrophages (moMACs), and moDCs, and the administration of 50 μM DMT prevented this increase in all cell types (Figures 3A,B)
Summary
Thought to be an opioid receptor, the sigma-1 receptor (Sig-1R) is classified as member of an orphan family after Su and colleagues had characterized the structural and biochemical features of the ligand binding site and identified the class as a non-opioid one (Su, 1982; Su et al, 1988) Later, based on their pharmacological characteristics and tissue expression, the distinction of Sig-1R and Sig-2R subtypes was proposed (Hellewell et al, 1994). Sig-1R is an endoplasmic reticulum (ER) protein located on the mitochondria-associated endoplasmic reticulum membrane (MAM) where its main role is to regulate ATP synthesis through the regulation of Ca2+ signaling by primarily acting as a molecular chaperone (Hayashi and Su, 2007; Su et al, 2016). Upon cellular stress, including hypoxia or oxidative stress, Sig-1R interacts with numerous receptors, ion channels, kinases, and various master regulator proteins residing on the ER, MAM, nucleus, or even in the cytosol to mobilize and fine-tune antistress responses
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