Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression.

David Aguinaga,Mireia Medrano,Katia Gysling,Enric I Canela,Rafael Franco,Ignacio Vega-Quiroga,Gemma Navarro

doi:10.3389/fnmol.2018.00017

Abstract

Sigma σ1 and σ2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by σ1R interacting with dopamine D1 and D2 receptors, the potential regulation of dopaminergic transmission by σ2R is also unknown. We here demonstrate that σ2R may form heteroreceptor complexes with D1 but not with D2 receptors. Remarkably σ1, σ2, and D1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of σ2R induces bias in signal transduction as σ2R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via σ1R, suggest that the D1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by σ1, σ2, and D1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit.

Highlights

In advanced societies cocaine addiction is an important health and socio-economic problem
When a similar experiment was performed expressing a constant amount of D1-Rluc and of σ2R-YFP and increasing amounts of non-fused σ1R, the results indicated that low expression levels of σ1R increased bioluminescence resonance energy transfer (BRET) signals; higher expression levels σ1R were able to displace σ2R out of the heteromer, as reflected by a significant decrease in BRET signal (Figure 2F)
When HEK-293T cells were transfected with D1R and siRNA for σ2R, the results indicated that cocaine pretreatment potentiated agonist-induced cAMP levels, which was evidence of cocaine action upon binding to the σ1R (Figure 3B)

Summary

Introduction

In advanced societies cocaine addiction is an important health and socio-economic problem. Sigma Receptors, Cocaine and Dopamine to other structures, such as the basal ganglia (Wise, 1984; Bradberry, 2008). There is strong evidence showing that cocaine exerts effects by a direct interaction with sigma receptors. Sigma-2 receptor (σ2R) was identified as a member of the family of membrane-associated progesterone receptors; apart from σ2R (PGRMC1), three other human members are identified: PGRMC2, neuferricin, and neudesin. They are haem proteins displaying a cytochrome b5-fold domain. The interaction of σ1R with dopamine receptors and the relevant role that σ1R exerts on the modulation of dopaminergic signaling by cocaine has been reported. No study has been undertaken to know whether the binding of cocaine to σ2R results in dopaminergic regulation

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