Apomorphine differentially engages the cAMP and β-arrestin signaling pathways relative to dopamine at human dopamine...

Apomorphine is the only dopamine agonist used to treat Parkinson disease with similar efficacy to levodopa. Its original characterization as a dopamine agonist was based on its receptor binding profile and capacity to recruit G proteins; however, current knowledge of G protein-coupled receptors highlights the importance of β-arrestin signaling to dopamine receptor functionality and expression. This study systematically compared the activity of apomorphine and dopamine across the range of dopamine receptor subtypes using biosensor assays that assessed its functional effects on both the cAMP and β-arrestin signaling pathways. Apomorphine facilitated cAMP signaling at both D1 and D2 family receptors with similar efficacy to dopamine but greater potency except at D3 receptors, where it exhibited similar potency. Apomorphine also recruited β-arrestin at all dopamine receptors similar to dopamine but with lower maximal effects at D1, D4, and D5 receptors. The potent efficacy of apomorphine on cAMP signaling at all dopamine receptor subtypes may explain its similar efficacy to levodopa. The clinical impact of the β-arrestin effects requires further study but is likely to influence its pharmacodynamic effects, including differences in adverse event profile compared to levodopa and D2-preferring agonists.