The Signaling and Pharmacology of the Dopamine D1 Receptor

Abstract

The dopamine D1 receptor (D1R) is a Gα_s/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gα_s or Gα_olf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.

Keywords: G protein-coupled receptors; Parkinson's Disease; biased agonism; cognitive impairment (CI); dopamine D1 receptor; drug development; intracellular signaling.

Figure 1

Chemistry and pharmacology of D1R ligands. Chemical structures, pharmacodynamic properties, and tested applications of representative ligands from the principal D1/D5R agonist classes.

Figure 2

Effector coupling of the D1R. Shown are the main interactions of the D1R with three sets of downstream effectors/modulators. Regulatory interactions that have not been fully elucidated, or for which contradictory evidence exists, are indicated with a “?”. Binding of a ligand such as dopamine (DA) activates G protein-dependent (Left) signaling through multiple effectors. Desensitization of the receptor (Center) is mediated by phosphorylation (P) of the C terminal tail and intracellular loops by GRKs and PKA. β-arrestin binding to the phosphorylated receptor (Right) mediates desensitization, internalization, and potentially additional intracellular signaling events generated through the activation of ERK1/2 and Src protein kinases.

Figure 3

Signaling downstream of the D1R. Shown is the network of core signaling pathway interactions downstream of D1R activation in striatal neurons, with a focus on phosphorylation-dependent (P) actions mediated by PKA. Activation is indicated by a black arrowed line, inhibition by a red line.