Daniel Felsing, PhD
Kinetics of Ligand Binding as a Basic Mechanism Driving Biased Signaling of Novel Dopamine D1 Receptor Agonists
Summary
Dopamine (DA) is a neurotransmitter acting through five G protein-coupled receptors (GPCRs) to modulate multiple physiological functions. Abnormal dopaminergic neurotransmission underlies the pathophysiology of several neuropsychiatric diseases. Recently, transformative research indicates that GPCRs signal not only via G protein-dependent mechanisms but also via G protein-independent interactions with Beta-arrestins. Ligands that activate GPCRs to signal specifically to one of these pathways are termed “biased ligands,” which provide the opportunity to fine tune GPCR activity with potentially superior therapeutic efficacy. This proposal is focused on understanding the mechanismof-action of novel agonist ligands targeting the dopamine D1 receptor (D1R). D1R agonists have long been pursued as a therapeutic target for treating neurological and psychiatric disorders (esp., Parkinson’s disease), but drug-like agonist ligands have remained elusive. Pfizer recently discovered the first drug-like D1R agonists that show signaling bias for activating G-s/cAMP signaling in the absence of Beta-arrestin signaling and receptor desensitization. The mechanism by which these new ligands cause biased signaling is unknown. This project Hypothesizes that the kinetics of ligand binding of D1R agonists is a driving factor that determines signaling bias towards G proteins or Betaarrestins. This research project will expand currently limited knowledge of ligand properties and mechanisms governing biased signaling at GPCRs.
