The Role of G-proteins and G-protein Regulating Proteins in Depressive Disorders

Abstract

Progress toward new antidepressant therapies has been relatively slow over the past few decades, with the result that individuals suffering from depression often struggle to find an effective treatment – a process often requiring months. Furthermore, the neural factors that contribute to depression remain poorly understood, and there are many open questions regarding the mechanism of action of existing antidepressants. A better understanding of the molecular processes that underlie depression and contribute to antidepressant efficacy is therefore badly needed. In this review we highlight research investigating the role of G-proteins and the regulators of G-protein signaling (RGS) proteins, two protein families that are intimately involved in both the genesis of depressive states and the action of antidepressant drugs. Many antidepressants are known to indirectly affect the function of these proteins. Conversely, dysfunction of the G-protein and RGS systems can affect antidepressant efficacy. However, a great deal remains unknown about how these proteins interact with antidepressants. Findings pertinent to each individual G-protein and RGS protein are summarized from in vitro, in vivo, and clinical studies.

RGS2 drives male aggression in mice via the serotonergic system

“…Previous investigations suggest that individuals with depressed Rgs2 levels may be potentially at risk for anxiety- or depressive-like related disorders, which can manifest aggressive behavior. A patient study from suicide victims observed increased levels of RGS2 in prefrontal cortex and amygdala regions, which may suggest that anxiety- and depression-related disorders in humans could be mediated through other areas of the brain 49 . Moreover, linkage studies in humans with RGS6, 7, 8, 5, 19, and 12 implicate their involvement in anxiety, depression, bipolar disorders, and/or schizophrenia.…”

“…Moreover, linkage studies in humans with RGS6, 7, 8, 5, 19, and 12 implicate their involvement in anxiety, depression, bipolar disorders, and/or schizophrenia. Since only Rgs2 , 13 , 14 , and Gα-interacting protein ( Gaip ) mRNAs were found in the DRN rat brain, other RGS proteins may be mediating their depressive and anxious behaviors outside the DRN, such as via the nucleus accumbens, amygdala, prefrontal cortex, or hippocampus 49,50 . Besides a plethora of data linking changes in 5HT levels to anxiety phenotypes, our data suggest that RGS2 modulates anxiety outside the serotonergic system.…”

Orphan G Protein Coupled Receptors in Affective Disorders

“…The large GPCR family constitutes the most exploited drug target in the human genome [ 31 , 32 ]. For instance, GPCRs mediate the signaling of neurotransmitters that are targeted by the action of many antidepressants [ 33 , 34 ]. Specifically, treatments with selective serotonin reuptake inhibitors (SSRI) and norepinephrine reuptake inhibitors (NRI), the most common classes of antidepressants, result in an indirect stimulation of serotonin (5-HT) and norepinephrine (NE) GPCRs.…”

“…However, the pharmacological targeting of single receptors failed to prove an efficient therapy in clinical trials. Over the years, many more GPCRs have been explored as pharmacological targets for the action of novel antidepressants or have been associated with the pathophysiology of MDD and anxiety [ 33 , 37 , 38 , 39 ]. Orphan GPCRs (oGPCRs) constitute a subfamily of GPCRs whose endogenous ligands have not yet been identified.…”

Regulators of G Protein Signaling in Analgesia and Addiction

“…Regulators of G protein signaling (RGS) proteins are multifunctional signal transduction molecules playing dynamic roles in physiological processes such as cardiac function, responses to stress, and cognition (Senese, Rasenick, & Traynor, 2018;Squires, Montanez-Miranda, Pandya, Torres, & Hepler, 2018;Terzi, Stergiou, King, & Zachariou, 2009;Traynor & Neubig, 2005;Wieland, Lutz, & Chidiac, 2007). RGS proteins modulate dopamine, noradrenergic, serotonin, opioid, muscarinic, metabotropic glutamate, adenosine, and other G protein coupled receptors (GPCRs) in central and peripheral cells.…”