Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders

Figures

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  Figure 1. Schematic illustration of G protein-coupled receptor (GPCR) signaling. (A) Canonical G protein-coupled receptor (GPCR) signaling occurs through heterotrimeric G proteins (Gα, Gβ, and Gγ). Upon GPCR activation, the Gα and Gβγ subunits dissociate and can induce each downstream signaling. Gα proteins can be subdivided into four types of families with different signaling components including adenylyl cyclase (AC) for Gs and Gi, phospholipase C (PLC) for Gq, Rho for G12. Gβ and Gγ subunits further diversify into distinct signaling responses such as PLC, phosphatidylinositol 3-kinase (PI3K), and protein kinase D (PKD) pathways. In a noncanonical GPCR pathway, arrestins (Arr) bind to the activated receptor that has been phosphorylated by G protein-coupled receptor kinases (GRKs). This leads to desensitization of G protein signaling by the receptor internalization and endocytosis. Meanwhile, this signaling can elicit additional intracellular responses including mitogen-activated protein kinase (MAPK) activation. (B) D2 dopamine receptor (D2R) activation stimulates a Gi/o protein that decreases intracellular cAMP in striatopallidal medium-sized spiny neurons (MSNs). This negatively…

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  Figure 2. Model of GPCR-mediated NMDA receptor pathways in striatopallidal MSNs. Gs-coupled GPCRs potentiate NMDA receptor activity through phosphorylation of its receptor via cAMP/PKA. Gs-coupled GPR6, GPR52, and A2a receptors, and Gi/o-coupled GPR88 are expressed in striatopallidal MSNs. Activated Gi/o-coupled D2R and GPR88 inhibit NMDA receptor activity through inhibition of cAMP/PKA signaling.

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  Figure 3. Proposed antipsychotic actions to confer bias of GPCR signaling. D2R-mediate Gi/o and β-arrestin2 (βarr2) pathways in striatopallidal MSNs (A–C). First-generation (FGA) and second-generation antipsychotics (SGA) antagonize both of these two pathways (B). Aripiprazole (Ari) functions as a partial agonist/antagonist at D2R-Gi/o signaling, whereas it fully antagonizes D2R-βarr2 signaling (C). Quetiapine (QUE) blocks 5-HT2A-βarr2 signaling and activates 5-HT2A-Gq signaling. Quetiapine also activates epidermal growth factor receptor (EGFR)-ERK pathway (D).

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  Figure 4. Potential therapeutic benefits of Selective D2R-β-arrestin2 ligands in prefrontal cortex and basal ganglia in schizophrenia. β-arrestin2 (βarr2)-biased ligands, such as UNC9994, can act as a D2R-βarr2 agonist in the hypodopaminergic prefrontal cortex but a D2R-βarr2 antagonist on hyperdopaminergic tone of striatopallidal MSNs. (A) In the hypodopaminergic state in the prefrontal cortex (PFC), D2R-βarr2 ligands can act as an agonist, which evokes action potential firing of cortical GABAergic fast-spiking interneurons (FSIs) and promotes neurite outgrowth through the AKT/GSK3β pathway. In parallel, the reduced Gi activity induces the rise of intracellular cAMP levels, resulting in the transcriptional changes of neuronal plasticity-related genes including egr-1, and Bdnf. This cAMP increase also potentiates NMDA receptor activity through cAMP/PKA, eventually leading to transcriptional changes. These events would participate in long-lasting effects on the neuronal circuit to ameliorate cognitive impairment in the disorder. (B) In the hyperdopaminergic state of striatopallidal MSNs, D2R-βarr2 ligands can act as antagonists, promoting heterodimerization of A2a receptor (A2A) with D2R…