Dopamine Receptors: Neurotherapeutic Targets for Substance Use Disorders

Nilson, Ashley N.; Felsing, Daniel E.; Allen, John A.

doi:10.1002/9781119564782.ch19

Cited by 1 publication

(2 citation statements)

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“…The dopamine D1 receptor (D1R) is a G protein-coupled receptor (GPCR) that regulates voluntary movement, working memory, attention and reward (Arnsten et al, 2017; Beaulieu and Gainetdinov, 2011; Dichter et al, 2012; Girgis et al, 2016; Goldman-Rakic et al, 2004; Nutt et al, 2015). The D1R is a validated drug target with the potential to treat motor deficits in Parkinson’s disease, impaired working memory, and reward pathway dysfunction in neuropsychiatric disorders (Arnsten et al, 2017; Beaulieu and Gainetdinov, 2011; Dichter et al, 2012; Nilson et al, 2022). The D1R couples to Gs/Golf G proteins that activate adenylyl cyclase to stimulate cyclic adenosine monophosphate (cAMP) production (Beaulieu and Gainetdinov, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…The related dopamine D5 receptor (D5R) is a highly homologous receptor that functions similarly to the D1R. In addition, agonist activation of the D1R recruits the multi-functional adaptor protein β-arrestin to the receptor, which can induce D1R desensitization and receptor endocytosis (Beaulieu and Gainetdinov, 2011; Kim et al, 2004; Nilson et al, 2022; Vickery and von Zastrow, 1999), which may support continued D1R-G protein signaling at endosomes (Irannejad et al, 2013; Kotowski et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Functionally selective dopamine D1 receptor endocytosis and signaling by catechol and non-catechol agonists

Nilson,

Felsing,

Wang

et al. 2024

Preprint

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The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective non-catechol D1R agonists were recently discovered and unexpectedly many of these ligands showed G protein biased signaling. Here, we investigate both catechol and non-catechol D1R agonists to validate potential biased signaling and examine if this impacts agonist-induced D1R endocytosis. We determined that most, but not all, non-catechol agonists display G protein biased signaling at the D1R and have reduced or absent Beta-arrestin recruitment. A notable exception was compound (Cmpd) 19, a non-catechol agonist with full efficacy at both D1R-G protein or D1R Beta-arrestin pathways. In addition, the catechol ligand A-77636 was a highly potent, super agonist for D1R Beta-arrestin activity. When examined for agonist-induced D1R endocytosis, balanced agonists SKF-81297 and Cmpd 19 induced robust D1R endocytosis while the G protein biased agonists did not. The Beta-arrestin super agonist, A-77636, showed significantly increased D1R endocytosis. Moreover, Beta-arrestin recruitment efficacy of tested agonists strongly correlated with total D1R endocytosis. Taken together, these results indicate the degree of D1R signaling functional selectivity profoundly impacts D1R endocytosis regardless of pharmacophore. The range of functional selectivity of these D1R agonists will provide valuable tools to further investigate D1R signaling, trafficking and therapeutic potential.

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