Review
The Akt–GSK-3 signaling cascade in the actions of dopamine

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Drugs that act on dopamine neurotransmission are important tools for the management of multiple neuropsychiatric disorders. Classically, dopamine receptors have been shown to regulate cAMP–PKA (protein kinase A) and Ca2+ pathways through G-protein-mediated signaling. However, it has become apparent that, in addition to this canonical action, D2-class dopamine receptors can function through a protein kinase B (Akt)–GSK-3 (glycogen synthase kinase 3) signaling cascade. This novel signaling mode involves the multifunctional scaffolding protein β-arrestin 2, which has a role in G-protein-coupled receptor (GPCR) desensitization. In this article, we provide an overview of how this dual function of components of the GPCR desensitization machinery relates to dopamine-receptor-mediated responses and we summarize recent insights into the relevance of the Akt–GSK-3 signaling cascade for the expression of dopamine-associated behaviors and the actions of dopaminergic drugs.

Introduction

Dopamine receptors are prototypic examples of G-protein-coupled receptors (GPCRs) mediating slow neurotransmission 1, 2. Dopamine has an important role in the modulation of fast glutamate- and GABA-mediated neurotransmission and is involved in crucial brain functions such as movement, emotion, reward and affect 2, 3, 4. Consequently, drugs acting on dopamine neurotransmission have become widely used tools for the management of multiple neuropsychiatric disorders, including schizophrenia, mood disorders, Parkinson's disease, attention deficit hyperactivity disorder (ADHD) and Tourette syndrome 2, 3, 4. A major dopamine-containing region of the brain, the nigrostriatal system, comprises dopamine-containing neurons that arise from the substantia nigra and the ventral tegmental area, which project to GABA-containing medium spiny neurons in the caudate putamen and nucleus accumbens (striatum) [5].

Classically, the functions of dopamine receptors have been associated with the regulation of cAMP–PKA (protein kinase A) through G-protein-mediated signaling 1, 2. Two classes of GPCR mediate dopamine functions. The D1 class of receptors (D1 and D5 receptors) couple mostly to Gαs and stimulate the production of the second messenger cAMP and the activity of PKA. By contrast, the D2 class of receptors (D2, D3 and D4 receptors) couple to Gαi/o to regulate the production of cAMP negatively, thus resulting in a diminution of PKA activity [1] (Figure 1). D2-class receptors also modulate intracellular Ca2+ levels by acting on ion channels or by triggering the release of intracellular Ca2+ stores 1, 2. Downstream from PKA, dopamine- and cAMP-regulated phosphoprotein with molecular weight 32 (DARPP-32) has important functions in regulating the efficacy of dopamine receptor signaling and its integration with other signaling modalities [2]. Furthermore, extracellular-signal-regulated kinase (ERK) has also been identified as an important mediator of cAMP signaling that is involved in the development of acute and chronic responses to dopaminergic drugs 6, 7, 8.

Recent investigations have shown that, apart from their canonical actions on G-protein-mediated signaling and the regulation of the cAMP–PKA pathway, dopamine receptors exert their effects in vivo through cAMP-independent mechanisms. This new mode of dopamine receptor signaling involves proteins that have classically been implicated in GPCR desensitization 9, 10. Moreover, cAMP-independent dopamine receptor signaling displays different kinetic properties and might serve as an integrator of dopamine receptor signaling and signaling events that emanate from other neurotransmitter receptors.

In this article, we provide an overview of recent advances in the characterization of the dual functions of dopamine-receptor-desensitizing mechanisms that act at the same time as terminators and mediators of different modalities of dopamine receptor signaling. We also highlight the potential relevance of the novel signaling mechanism that involves the protein kinase B (Akt)–GSK-3 (glycogen synthase kinase 3) pathway (Box 1) for the expression of dopamine-associated behaviors and the action of dopaminergic drugs.

Section snippets

Receptor desensitization mechanisms

Following receptor stimulation, GPCR signaling is rapidly inactivated by a series of mechanisms that results in receptor desensitization, internalization and termination of signaling. GPCR activation leads to the rapid phosphorylation of the receptors by members of a family of GPCR kinases (GRKs) 11, 12, 13, 14. The phosphorylation of receptors by GRKs leads to the recruitment of scaffolding proteins termed arrestins, resulting in the uncoupling of the receptors from G proteins 13, 14, 15 (

Role of GRKs in the regulation of dopamine functions

Studies of dopamine receptor function in mice lacking different GRKs have, in most cases, supported a role for these kinases in both GPCR desensitization and signaling [13]. The seven GRKs in mammals (GRK1–GRK7) belong to three classes: GRK1-like, GRK2-like and GRK4-like [13]. Whereas GRK1 (rhodopsin kinase) and GRK7 (iodopsin kinase) are found primarily in the retina and are involved in the termination of phototransduction by opsins, GRK2, GRK3, GRK4, GRK5 and GRK6 are widely expressed in the

Role of β-arrestin 2 in cAMP-independent dopamine receptor signaling and function

Several lines of evidence indicate that, in addition to their canonical action on G proteins, GPCRs can also activate signaling through molecules that are classically involved in the regulation of GPCR desensitization [25] (Figure 1a). Evidence from heterologous cellular systems demonstrates that β-arrestins can act as G-protein-independent mediators of signaling by scaffolding other proteins such as kinases and their substrates 18, 20, 25. However, the implication of β-arrestin-mediated

Involvement of Akt and GSK-3 in the action of psychotropic drugs

Typical antipsychotics such as haloperidol are thought to exert most of their actions by blocking D2-class receptors, thus supporting a role for dopamine neurotransmission in the etiology of schizophrenia. Recent genetic association studies have established a link between a deregulation of Akt signaling and schizophrenia. Following transmission–disequilibrium tests, a major association of Akt1 haplotypes with schizophrenia has been reported in several independent cohorts of schizophrenic

Future perspectives

The characterization of the mechanisms by which β-arrestins and GRKs contribute to dopamine receptor signaling is at an early stage and it would be naïve to believe that the complete palette of molecular responses associated with these molecules has been identified. Of particular interest, the further characterization of GRKs and other modulators of β-arrestins in the dopamine system might enable researchers to determine the functions of these molecules in regulating the positive and negative

Acknowledgements

This work was supported in part by National Institutes of Health grants DA-13511, NS-19576, MH-73853 and MH-40159 (to M.G.C.). M.G.C. is the Lattner Foundation National Alliance for Research on Schizophrenia and Depression (NARSAD) Distinguished Investigator. J-M.B. is the NARSAD Southwest Florida Investigator and the recipient of a fellowship from the Canadian Institutes of Health Research.

References (62)

  • S.G. Schwab

    Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families

    Biol. Psychiatry

    (2005)
  • M. Ikeda

    Association of AKT1 with schizophrenia confirmed in a Japanese population

    Biol. Psychiatry

    (2004)
  • Z. Zhao

    Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction

    Schizophr. Res.

    (2006)
  • U.G. Kang

    The effects of clozapine on the GSK-3-mediated signaling pathway

    FEBS Lett.

    (2004)
  • H. Alimohamad

    Antipsychotics alter the protein expression levels of β-catenin and GSK-3 in the rat medial prefrontal cortex and striatum

    Biol. Psychiatry

    (2005)
  • F. Karege

    Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3β in ventral prefrontal cortex of depressed suicide victims

    Biol. Psychiatry

    (2007)
  • F. Zhang

    Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3

    J. Biol. Chem.

    (2003)
  • P. De Sarno

    Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium

    Neuropharmacology

    (2002)
  • F.D. Smith

    Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein

    J. Biol. Chem.

    (1999)
  • J. Kang

    A nuclear function of β-arrestin 1 in GPCR signaling: regulation of histone acetylation and gene transcription

    Cell

    (2005)
  • J. Stelling

    Robustness of cellular functions

    Cell

    (2004)
  • M.J. Chen et al.

    Exercise activates the phosphatidylinositol 3-kinase pathway

    Brain Res. Mol. Brain Res.

    (2005)
  • S. Ahn

    Differential kinetic and spatial patterns of β-arrestin and G protein-mediated ERK activation by the angiotensin II receptor

    J. Biol. Chem.

    (2004)
  • C. Missale

    Dopamine receptors: from structure to function

    Physiol. Rev.

    (1998)
  • P. Greengard

    The neurobiology of slow synaptic transmission

    Science

    (2001)
  • A. Carlsson

    A paradigm shift in brain research

    Science

    (2001)
  • L. Heimer

    Basal ganglia

  • E. Valjent

    Role of the ERK pathway in psychostimulant-induced locomotor sensitization

    BMC Neurosci.

    (2006)
  • E. Valjent

    Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • J.M. Beaulieu

    Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • J.L. Arriza

    The G-protein-coupled receptor kinases βARK1 and βARK2 are widely distributed at synapses in rat brain

    J. Neurosci.

    (1992)
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