GSK-3β activity and hyperdopamine-dependent behaviors

Abstract

Dopamine plays important roles in normal brain function and many neuropsychiatric disorders. Classically, dopamine receptors are positively coupled to G protein-mediated signaling to regulate cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and Ca(2+) pathways. However, emerging evidence indicates that under hyperdopaminergic conditions, the protein kinase B (Akt)-glycogen synthase kinase 3β (GSK-3β) signaling cascade may mediate dopamine actions via D(2)-like receptors. This cAMP-independent signaling pathway involves the regulation of downstream synaptic targets, e.g., AMPA receptor, NMDA receptors, and thus synaptic plasticity. Here we provide an overview of how this novel signaling pathway relays dopamine receptor-mediated responses, particularly hyperdopamine-dependent behaviors. We discuss the relevance of the Akt/GSK-3β signaling cascade for the expression of dopamine-dependent behaviors and the drug actions associated with dopaminergic systems.

Figure 1

Model illustrating the signaling pathways activated by optimal DA and hyperdopamine. A, under normal conditions, optimal DA through activation of D1-coupled Gs/olf protein activates the classic AC/cAMP/PKA/DARPP-32 pathway, which reduces the activity of protein phosphatase 1 (PP1). In addition, phosphorylation of DARPP-32 by Cdk5 causes inhibition of PKA, inactivation of protein phosphatase 2A (PP2A), and decreased dephosphorylation of DARPP-32. Inhibition of PKA also results in decreased phosphorylation of DARPP-32 and, therefore, inactivation of PP1. Inhibition of PKA and activation of PP1 synergistically regulate the phosphorylation of various substrates, such as AMPA and NMDA receptors, and thus induce long-term plasticity and enhance cognitive functions. B, under hyperdopaminergic conditions, however, the signaling pathways activated by DA are much more complicated. On the one hand, by sequentially activating DA D1 receptors, PKA and PP2A reduce the level of DARPP-32. Dephosphorylation of DARPP-32 by PP-2A removes the inhibition of PKA. Activation of PKA also results in increased phosphorylation of DARPP-32 and inhibition of PP1. Activation of PKA and inhibition of PP1 synergistically increase the phosphorylation of various substrates such as glutamate receptors. On the other hand, emerging evidence indicates that a high concentration of DA likely activates D2 receptors more than it does D1 receptors. Under hyperdopaminergic conditions, Akt/GSK-3β signaling cascade critically mediates DA actions via D₂-like receptors. This cAMP-independent signaling pathway involves β-arrestin and PP2A in the upstream and regulation of glutamate receptors and synaptic plasticity in the downstream. Consequently, increase of GSK-3β activity would cause a cognitive deficit. In the striatum, it has also been reported that under a high concentration of DA, the D1/D2 heterooligomer couples to Gq/11 or Gβγ to activate the phospholipase C/IP3/PP2B pathway and to regulate synaptic functions.