New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy

Abstract

The dopamine D₂ receptor (D₂R) is a G protein-coupled receptor that is a common target for antipsychotic drugs. Antagonism of D₂R signaling in the striatum is thought to be the primary mode of action of antipsychotic drugs in alleviating psychotic symptoms. However, antipsychotic drugs are not clinically effective at reversing cortical-related symptoms, such as cognitive deficits in schizophrenia. While the exact mechanistic underpinnings of these cognitive deficits are largely unknown, deficits in cortical dopamine function likely play a contributing role. It is now recognized that similar to most G protein-coupled receptors, D₂Rs signal not only through canonical G protein pathways but also through noncanonical beta-arrestin2-dependent pathways. We review the current mechanistic bases for this dual signaling mode of D₂Rs and how these new concepts might be leveraged for therapeutic gain to target both cortical and striatal dysfunction in dopamine neurotransmission and hence have the potential to correct both positive and cognitive symptoms of schizophrenia.

Keywords: Antipsychotics; Arrestin; Dopamine; Functional selectivity; Schizophrenia; System bias.

Figure 1. Functional Selectivity at dopamine D2Rs

A) Functional selectivity at D2Rs can be regulated by the chemical structure of the ligand (shown dopamine and UNC9994) or conformations of the receptor or the complement of intracellular transducer proteins such as G proteins (Gαβγ), GPCR kinases (GRK) or β-arrestins (βarr). B) Bioluminiscence resonance energy transfer (BRET) assay for detection of βarr2 recruitment to D2Rs by dopamine (DA), aripiprazole (ARI) or UNC9994 (94A) in HEK293T cells with i) endogenous or ii) over-expression of GRK2 shows that over-expression of GRK2 renders ARI and 94A as partial agonists.

Figure 2. Simplified circuit schematic of the dopamine (DA) hypothesis of schizophrenia (SCZ) and implications of biased D2R signaling

As depicted in sagittal sections of a mouse brain, under normal conditions (upper panel) DA in the prefrontal cortex (PFC) through DA receptors (DARs) regulates firing of fast-spiking GABAergic parvalbumin+ interneurons (FSIs) that regulate rhythmic firing of glutamate (Glu) releasing pyramidal neurons (PYR). The PYR neurons presumably regulate neuronal activity of either striatal (STR) medium spiny neurons (MSNs), which express NMDA receptors (NMDARs) and DARs, or midbrain substantia nigra pars compacta (SN) neurons that also release DA onto striatal MSNs. In conditions that mimic schizophrenia (SCZ, middle panel), a loss of PFC DA (hypodopaminergia) or inhibition of neuronal activity of FSIs leads to over-excitability of PYRs. The enhanced activity of PYRs could presumably lead to enhanced striatal MSN activity directly or through increased DA release (hyperdopaminergia) in the striatum by SN neurons. A β-arrestin2 (βarr2) biased partial agonist like UNC9994 that acts as an agonist in the PFC but as an antagonist in the striatum could represent an ideal APD-like compound that could simultaneously reverse both hypo- and hyperdopaminergia in schizophrenia (SCZ+APD, lower panel). The proposed mechanism of such a compound would be to enhance βarr2/GRK2 but reduce Gαi activity in the PFC and inhibit βarr2/GRK2 activity in the striatum. Normal activity ( ), enhanced activity ( ) and reduced activity ( ).