Biological And Biochemical Characterization Of Sigma Receptors

自1982年我在NIDA IRP的实验室发现sigma-1受体以来，许多临床前研究表明，sigma-1受体及其相关配体与中风、健忘症、抑郁症、癌症、阿尔茨海默病、疼痛和可卡因成瘾有关。

In the years since my laboratory at the NIDA IRP identified the sigma-1 receptor in 1982, many preclinical studies have shown that sigma-1 receptors and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimers disease, pain, and cocaine addiction. In this fiscal year, 2019-2020, we made a fundamental discovery on the new action of cocaine. Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue, we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs. We also made a fundamental mechanistic finding that in addition to acting on traditionally recognized receptors or transporters on the plasma membrane, several drugs of abuse, including amphetamine, methamphetamine, nicotine, opioid, cocaine, ketamine, and cannabinoid can work to exert their effects by acting on additional molecular targets either on the plasma membrane or inside a cell. These targets are usually nascent receptors or proteins that can cause downstream signaling or molecular events, leading to altered physiological outcomes favoring addictive processes. However, those non-canonical targets of drugs of abuse, in general, have not been widely recognized in drug abuse research. This perspective diverts attention to those underrecognized targets, in the hope of promoting a more complete understanding of the action of drugs of abuse.