Zinc Is Involved in Depression by Modulating G Protein-Coupled Receptor Heterodimerization

Abstract

5-Hydroxytryptamine 1A receptor and galanin receptor 1 belong to the G-protein-coupled receptors superfamily and they have been described to heterodimerize triggering an anomalous physiological state that would underly depression. Zinc supplementation has been widely reported to improve treatment against major depressive disorder. Our work has focused on the study and characterization of these receptors and its relationships with zinc both under purified conditions and in cell culture. To this aim, we have designed a strategy to purify the receptors in a conformationally active state. We have used receptors tagged with the monoclonal Rho-1D4 antibody, and employed ligand assisted purification in order to successfully purify both receptors in a properly folded and active state. The interaction between both purified receptors has been analyzed by surface plasmon resonance in order to determine the kinetics of dimerization. Zinc effect on heteromer has also been tested using the same methodology, but exposing the 5-hydroxytryptamine 1A receptor to zinc before the binding experiment. These results, combined with FRET measurements, in the absence and presence of zinc, suggest that this ion is capable of disrupting this interaction. Moreover, molecular modelling suggests that there is a coincidence between zinc binding sites and heterodimerization interfaces for the serotonin receptor.Our results establish a rational explanation for the role of zinc in the molecular processes associated with receptor-receptor interactions and its relationship with depression, in agreement with previously reported evidence for the positive effects of zinc in depression treatment, and the involvement of our target dimer in the same disease.

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

“…The role of zinc in depression and antidepressant therapy was emphasized in numerous preclinical and clinical studies, but the precise mechanism of this action is not understood [ 28 – 30 , 56 – 59 ]. It has been suggested that the effects of zinc can also be mediated by the serotonergic system [ 28 , 60 – 62 ], among others, and the presence of endogenous Zn 2+ binding sites in 5-HT 1A receptors, together with its allosteric regulation, has been demonstrated [ 6 , 7 ].…”

“…Moreover, because the 5-HT 1A and 5-HT 7 receptors are co-expressed in various brain regions and their functional cross talk has been suggested in depressive disorders, possibly through heterodimerization [ 25 , 78 ], the fine-tuning of receptor-mediated signaling by zinc ions can be hypothesized. It has also been recently postulated that zinc plays a critical role in specific interactions between 5-HT 1A receptor and galanin receptor 1 by disrupting formation of pathological heterodimers in a depressive state [ 61 , 62 ]. Therefore, in future studies it would be interesting to analyze the involvement of zinc ions also in the process of 5-HT 1A /5-HT 7 receptor heterodimerization.…”

Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease

“…GPR39 is a GPCR belonging to class A and represents a zinc binding receptor (Holst et al, 2007 ). Recent results demonstrated that zinc can disrupt the GalR1-5-HT1A heteroreceptor complex which may contribute to its antidepressant actions (Tena-Campos et al, 2015 , 2016 ). In this process, GPR39 can form a dynamic heterotrimeric receptor complex with signaling diversity as demonstrated in cellular models (Tena-Campos et al, 2015 ).…”

Zinc in the Monoaminergic Theory of Depression: Its Relationship to Neural Plasticity

“…5-HT 1A and GalR 1 , which share the same signal transduction pathway (i.e., activate G α i protein which leads to inhibition of adenylyl cyclase), have been described to heterodimerize and functional characteristic of the heterodimers revealed absence of addictive effects what can be explained by the existence of allosteric antagonistic communication to avoid excessive inhibition of adenylyl cyclase [58]. Furthermore, zinc was found to disrupt the heterodimerization process of 5-HT 1A and GalR 1 [59]. Activities of the monohomomeric receptors: 5-HT 1A , GalR 1 , and GPR39, and the heteroreceptor complexes: 5-HT 1A -GPR39 and 5-HT 1A -GPR39-GalR 1 , were measured by their ability to activate response elements: the serum response element (SRE) and nuclear factor kappa beta response element (NF κβ -RE) [56].…”