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Functional Selectivity of Dopamine D₁ Receptor Signaling: Retrospect and Prospect.

ABSTRACT: Research progress on dopamine D₁ receptors indicates that signaling no longer is limited to G protein-dependent cyclic adenosine monophosphate phosphorylation but also includes G protein-independent β-arrestin-related mitogen-activated protein kinase activation, regulation of ion channels, phospholipase C activation, and possibly more. This review summarizes recent studies revealing the complexity of D₁ signaling and its clinical implications, and suggests functional selectivity as a promising strategy for drug discovery to magnify the merit of D₁ signaling. Functional selectivity/biased receptor signaling has become a major research front because of its potential to improve therapeutics through precise targeting. Retrospective pharmacological review indicated that many D₁ ligands have some degree of mild functional selectivity, and novel compounds with extreme bias at D₁ signaling were reported recently. Behavioral and neurophysiological studies inspired new methods to investigate functional selectivity and gave insight into the biased signaling of several drugs. Results from recent clinical trials also supported D₁ functional selectivity signaling as a promising strategy for discovery and development of better therapeutics.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8584964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Functional selectivity (or biased agonism) is a property exhibited by some G protein-coupled receptor (GPCR) ligands, which results in the modulation of a subset of a receptor's signaling capabilities and more precise control over complex biological processes. The dopamine D2 receptor (D2R) exhibits pleiotropic responses to the biogenic amine dopamine (DA) to mediate complex central nervous system functions through activation of G proteins and β-arrestins. D2R is a prominent therapeutic target for psychological and neurological disorders in which DA biology is dysregulated and targeting D2R with functionally selective drugs could provide a means by which pharmacotherapies could be developed. However, factors that determine GPCR functional selectivity in vivo may be multiple with receptors, ligands and transducers contributing to the process. We have recently described a mutagenesis approach to engineer biased D2R mutants in which G protein-dependent ([Gprot]D2R) and β-arrestin-dependent signaling ([βarr]D2R) were successfully separated (Peterson, et al. PNAS, 2015). Here, permutations of these mutants were used to identify critical determinants of the D2R signaling complex that impart signaling bias in response to the natural or synthetic ligands. Critical residues identified in generating [Gprot]D2R and [βarr]D2R conferred control of partial agonism at G protein and/or β-arrestin activity. Another set of mutations that result in G protein bias was identified that demonstrated that full agonists can impart unique activation patterns, and provided further credence to the concept of ligand texture. Finally, the contributions and interplay between different transducers indicated that G proteins are not aberrantly activated, and that receptor kinase and β-arrestin activities are inextricably linked. These data provide a thorough elucidation of the feasibility and malleability of D2R functional selectivity and point to means by which novel in vivo therapies could be modeled.

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Functional Selectivity of Dopamine D₁ Receptor Signaling: Retrospect and Prospect.

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OmicsDI is part of the ELIXIR infrastructure

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Functional Selectivity of Dopamine D₁ Receptor Signaling: Retrospect and Prospect.