When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor

Abstract

N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine-associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors.

Fig. 1

Hypothetical scheme illustrating the signaling of N,N-dimethyltryptamine through sigma-1 receptors. (A) Sigma-1 receptors (Sig-1Rs) at the mitochondrion-associated endoplasmic reticulum (ER) membrane (MAM) function as ligand-activated molecular chaperones, particularly when ligands are present at concentrations close to their affinities (34). Sig-1R ligands, including DMT, at concentrations close to their K_i values, cause the dissociation of Sig-1Rs from another ER chaperone, binding immunoglobulin protein (BiP) (34), allowing Sig-1Rs to chaperone inositol 1,4,5-trisphosphate receptors (IP₃Rs) at the MAM (34). This enhances Ca²⁺ signaling from the ER into mitochondria (34, 35), activates the tricarboxylic acid (TCA) cycle, and increases adenosine triphosphate (ATP) production (35). (B) Higher concentrations of DMT cause the translocation of Sig-1Rs from the MAM to the plasma membrane, leading to the inhibition of ion channels. Thus, Sig-1R ligands might shift the site of action of Sig-1R chaperones from the center of the cell to its periphery. In the present scheme, Sig-1Rs and related molecules or organelles are illustrated in the postsynaptic region for the sake of simplicity, although they may also be present presynaptically or in glia.