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

Yang Yang

doi:10.3390/ijms222111914

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.

Highlights

adenylate cyclase type 5 (AC5)-produced striatal Cyclic Adenosine Monophosphate (cAMP) binds to the regulatory subunits of protein kinase kinase A (PKA) that phosphorylates various proteins such as DARPP-32 and cAMP response element-binding protein (CREB). How this signaling leads to D1 -mediated behavioral effects is still unclear, these downstream molecules are involved in the regulation of gene expression [4]. These lines of evidence encouraged the development of functionally selective dopamine ligands whose cAMP signaling can be biased to the PKA subunit to provide a more targeted action improved therapeutic index
With the discovery of many novel signaling or sub-pathways related to D1 Rs, studies related to grasping the breadth of D1 R functional selectivity are expanding
Even though some reports at the time of publishing did not focus on functional selectivity, a retrospective review of their findings indicate they contributed to this field

Summary

A Brief Introduction of Functional Selectivity

The term functional selectivity [1] was first introduced in 1994 and soon thereafter other reports referred to this phenomenon alternately as “agonist trafficking of signaling”,. Others stimulated striatal or prefrontal cortex D1 Rs in vivo or in vitro with the D1 selective agonist SKF38393 and showed ERK1/2 was phosphorylated [24,27,28] These studies provided the initial evidence of D1 R-mediated β-arrestin signaling and its function through ERK1/2. Rap GTPase and promotes the MAP kinase cascade [7,31] These studies suggested there may be potential cross talk between D1 R-mediated cAMP and β-arrestin-related signaling. The most supportive evidence for D1 R-mediated PLC signaling came from studies using the D1 ligand SKF83959 that has small effects on adenylate cyclase but strong efficacy for PLC activation It induced contralateral rotations in the unilateral. The evidence suggests that D1 Rs may be independent of PLC activation

Insight on Functional Selectivity through the Implications of D1 Signaling

Progress on the Structural Biology of Dopamine Receptors

Potential of Receptor Localization-Related Functional Selectivity

Functionally Selective D1 Ligands

11. Summary