Figure 3. Potential Sig-1R-involved molecular mechanisms in the actions of cocaine and methamphetamine (METH).

Cocaine dissociates Sig-1R from Bip/GRP78 and activates the chaperone activity of Sig-1R. Sig-1R stabilizes IP3R leading to the increase of intracellular calcium concentration. Cocaine induces the translocation of Sig-1R from ER to the plasma membrane and the nuclear envelope, thus intensifying Sig-1R interaction with target proteins. At the plasma membrane, Sig-1R modulates the function of potassium channels by interacting with Kv1.2 subunit. At the nuclear envelope, cocaine through Sig-1R can promote the formation of the chromatin remodeling complex composed of emerin/HDAC/BAF that binds to suppress the gene transcription of MAOB. Cocaine or METH induces the ROS production and autophagy which can be inhibited by sigma receptor antagonists. Abbreviations: ER, endoplasmic reticulum; Mito, mitochondria; DA, dopamine; D1R, dopamine D1 receptor; TRPC, transient receptor potential canonical; IP3, inositol 1,4,5-triphosphate;IP3R, IP3 receptor; ROS, reactive oxygen species; ATP, adenosine triphosphate; BAF, barrier-to-auto autointegration factor; HDAC, histone deacetylase; MAOB, monoamine oxidase B; [Ca²⁺]_i, intracellular Ca²⁺ concentration; [Ca²⁺]_mito, mitochondrion Ca²⁺ concentration.