# Akt/GSK-3 Signaling Cascade and the Actions of Dopamine

> **NIH NIH R37** · DUKE UNIVERSITY · 2020 · $650,556

## Abstract

The various actions of dopamine (DA) on target neurons are mediated via prototypical 7-transmembrane G
protein-coupled receptors (GPCR) that couple to various effectors through G protein-dependent
mechanisms. However, it is now widely appreciated that GPCRs can also signal through the ability of the
adaptor protein βarrestin to scaffold signaling complexes that are distinct from canonical G protein signaling.
These dual signaling modes may enable what is commonly referred to as functionally selective or biased
signaling. We have shown before that the dopamine D2 receptor (D2R), which is the main target of clinically
effective antipsychotics, mediates some of its physiological effects through engagement of a
βarrestin2/Akt/PP2A/GSK3β signaling complex. During the initial portion of this R37 award, we have used
genetic, biochemical, and pharmacological approaches to provide concrete evidence that D2R/βarrestin2
signaling is important in behavioral responses following activation of the DA system. Interestingly, we
discovered using neuronally selective deletions of βarrestin2 in mice that an antipsychotic-like
D2R/βarrestin2 biased tool compound UNC9994A behaved as an antagonist in the striatum but an agonist in
the cortex. These results correlate with both higher levels of GPCR kinase and βarrestin2 in cortex versus
striatum and the ability of UNC9994A to reverse deficits in a mouse model of cognitive/sociability functions.
These results suggest that βarrestin2/D2R signaling may be an unappreciated means to control cognitive
and social domains of behavior in vivo. The goals of our R37 continuation application are to use the genetic
and biochemical tools we have developed, like G protein or βarrestin2 preferring mutant D2Rs, to identify cell
type specific molecular and biochemical mechanisms involved in the control of these behavioral domains.
Our Specific Aims are: 1) determine the impact of D2R biased signaling on cognitive domains in mice
reconstituted with biased D2R mutants; 2) identify the molecular and neuronal mechanisms underpinning the
cognitive and social effects and 3) assess how D2R biased signaling in the cortex controls neuronal
electrophysiology and affects downstream brain circuits to control cognitive and sociability functions.

## Key facts

- **NIH application ID:** 9843737
- **Project number:** 5R37MH073853-15
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Marc G. Caron
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,556
- **Award type:** 5
- **Project period:** 2016-01-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843737

## Citation

> US National Institutes of Health, RePORTER application 9843737, Akt/GSK-3 Signaling Cascade and the Actions of Dopamine (5R37MH073853-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843737. Licensed CC0.

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