Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders

Abstract

Among mental diseases, major depressive disorder (MDD) and anxiety deserve a special place due to their high prevalence and their negative impact both on society and patients suffering from these disorders. Consequently, the development of novel strategies designed to treat them quickly and efficiently, without or at least having limited side effects, is considered a highly important goal. Growing evidence indicates that emerging properties are developed on recognition, trafficking, and signaling of G-protein coupled receptors (GPCRs) upon their heteromerization with other types of GPCRs, receptor tyrosine kinases, and ionotropic receptors such as N-methyl-D-aspartate (NMDA) receptors. Therefore, to develop new treatments for MDD and anxiety, it will be important to identify the most vulnerable heteroreceptor complexes involved in MDD and anxiety. This review focuses on how GPCRs, especially serotonin, dopamine, galanin, and opioid heteroreceptor complexes, modulate synaptic and volume transmission in the limbic networks of the brain. We attempt to provide information showing how these emerging concepts can contribute to finding new ways to treat both MDD and anxiety disorders.

Molecular pathways of major depressive disorder converge on the synapse

“…Protein examples of these pathways include phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), Akt, mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK). Of the other receptors addressing these pathways, we focus on the opioid receptors, as they functionally interact with 5-HT and dopamine receptors through heterodimerization [ 45 ]. In general, opioid receptors negatively regulate neurotransmitter release and excitability of neurons by the activation of G-protein-mediated mechanisms, resulting in increased potassium channel functioning, cell depolarization, and inhibition of functioning voltage-gated calcium channels, negatively regulating neurotransmitter release [ 46 ].…”

The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: potential relevance for brain and behavior

“…See also the excellent review of Froemke and Young, which discusses the most recent findings on the neurocircuitry of oxytocin mainly in the context of social behavior (Froemke and Young, 2021 ). This integrative mechanism may be disturbed in mental diseases like depression and anxiety (Perez de la Mora et al, 2022 ).…”

“…Recently, the crystal structure of the human OXTR was established in a complex with the OXTR antagonist retosiban which is in clinical use for counteraction of labor (Waltenspuhl et al, 2020 ). It is of interest that the OXTR has a dependence on allosteric modulators like cholesterol and magnesium (Mg 2+ ) for full activation (Klein et al, 1995a , b ; Perez de la Mora et al, 2022 ). In the crystal structure, it was possible to observe that the cholesterol was bound in a pocket produced by transmembrane helices IV and V (Waltenspuhl et al, 2020 ).…”

“…The 5HT2AR agonist-induced allosteric inhibition of the oxytocin receptor protomer can diminish its increase in social behavior (Froemke and Young, 2021 ). The Oxytocin receptor protomer (OXTR) can upon activation allosterically inhibit 5-HT2AR protomer signaling and diminish the 5-HT2AR signaling with possible antidepressant effects since 5-HT2AR mediates depressive effects (Borroto-Escuela et al, 2021 ; Perez de la Mora et al, 2022 ). The oxytocin homo-receptor complex, shown as a homo dimer, is found in the center of the illustration, coupled to G alpha q.…”

“…However, the role of the GHS-R1a in the brain as a target for ghrelin is not clear, since penetration into the brain by ghrelin mainly may take place via rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons (Schaeffer et al, 2013 ) and over the median eminence open to the portal blood (Rodriguez et al, 2010 ). Moreover, the GHS-R1a possesses a high constitutive activity that reaches 50% of its maximal activity that can be modulated by dynamic expression and allosteric mechanisms in GPCR-GHS-R1a complexes (Holst et al, 2003 ; Petersen et al, 2009 ; Schellekens et al, 2013a , b ; Perez de la Mora et al, 2022 ). The novel GHS-R1a/OXTR pair was revealed by the Schellekens group using in vitro approaches and a novel flow cytometry-based fluorescence resonance energy transfer (fc-FRET) technique (Wallace Fitzsimons et al, 2019 ).…”