TRENDS in Pharmacological Sciences The Akt–GSK-3 signaling cascade inthe actions of dopamine Jean-Martin Beaulieu, Raul R. Gainetdinov and Marc G. Caron Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA Drugs that act on dopamine neurotransmission are in a diminution of PKA activity D2-class important tools for the management of multiple neurop- receptors also modulate intracellular Ca2+ levels by acting sychiatric disorders. Classically, dopamine receptors have on ion channels or by triggering the release of intracellular been shown to regulate cAMP–PKA (protein kinase A) and Ca2+ stores . Downstream from PKA, dopamine- and Ca2+ pathways through G-protein-mediated signaling.
cAMP-regulated phosphoprotein with molecular weight 32 However, it has become apparent that, in addition to this (DARPP-32) has important functions in regulating the canonical action, D2-class dopamine receptors can func- efficacy of dopamine receptor signaling and its integration tion through a protein kinase B (Akt)–GSK-3 (glycogen with other signaling modalities . Furthermore, extra- synthase kinase 3) signaling cascade. This novel signaling cellular-signal-regulated kinase (ERK) has also been ident- mode involves the multifunctional scaffolding protein b- ified as an important mediator of cAMP signaling that is arrestin 2, which has a role in G-protein-coupled receptor involved in the development of acute and chronic responses (GPCR) desensitization. In this article, we provide an to dopaminergic drugs overview of how this dual function of components of Recent investigations have shown that, apart from their the GPCR desensitization machinery relates to dopa- canonical actions on G-protein-mediated signaling and the mine-receptor-mediated responses and we summarize regulation of the cAMP–PKA pathway, dopamine recep- recent insights into the relevance of the Akt–GSK-3 sig- tors exert their effects in vivo through cAMP-independent naling cascade for the expression of dopamine-associated mechanisms. This new mode of dopamine receptor signal- behaviors and the actions of dopaminergic drugs.
ing involves proteins that have classically been implicatedin GPCR desensitization Moreover, cAMP-indepen- dent dopamine receptor signaling displays different kinetic properties and might serve as an integrator of dopamine G-protein-coupled receptors (GPCRs) mediating slow receptor signaling and signaling events that emanate from neurotransmission Dopamine has an important role other neurotransmitter receptors.
in the modulation of fast glutamate- and GABA-mediated In this article, we provide an overview of recent neurotransmission and is involved in crucial brain func- advances in the characterization of the dual functions of tions such as movement, emotion, reward and affect .
dopamine-receptor-desensitizing mechanisms that act at Consequently, drugs acting on dopamine neurotrans- the same time as terminators and mediators of different mission have become widely used tools for the manage- modalities of dopamine receptor signaling. We also high- ment of multiple neuropsychiatric disorders, including light the potential relevance of the novel signaling mech- schizophrenia, mood disorders, Parkinson's disease, atten- anism that involves the protein kinase B (Akt)–GSK-3 tion deficit hyperactivity disorder (ADHD) and Tourette (glycogen synthase kinase 3) pathway () for the syndrome . A major dopamine-containing region of expression of dopamine-associated behaviors and the the brain, the nigrostriatal system, comprises dopamine- action of dopaminergic drugs.
containing neurons that arise from the substantia nigraand the ventral tegmental area, which project to GABA- Receptor desensitization mechanisms containing medium spiny neurons in the caudate putamen Following receptor stimulation, GPCR signaling is rapidly and nucleus accumbens (striatum) .
inactivated by a series of mechanisms that results in recep- Classically, the functions of dopamine receptors have tor desensitization, internalization and termination of sig- been associated with the regulation of cAMP–PKA (protein naling. GPCR activation leads to the rapid phosphorylation kinase A) through G-protein-mediated signaling . Two of the receptors by members of a family of GPCR kinases classes of GPCR mediate dopamine functions. The D1 class (GRKs) . The phosphorylation of receptors by GRKs of receptors (D1 and D5 receptors) couple mostly to Gas and leads to the recruitment of scaffolding proteins termed stimulate the production of the second messenger cAMP arrestins, resulting in the uncoupling of the receptors from and the activity of PKA. By contrast, the D2 class of G proteins . Two arrestins, b-arrestin 1 receptors (D2, D3 and D4 receptors) couple to Gai/o to and b-arrestin 2, are expressed in most mammalian tissues, regulate the production of cAMP negatively, thus resulting including the brain, whereas two other proteins, the visualarrestins, are expressed specifically in retinal cones androds . The interaction of arrestins with GPCRs is fol- Corresponding author: Caron, M.G. ().
Available online 8 March 2007.
lowed by the recruitment of an endocytic complex, which 0165-6147/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:

TRENDS in Pharmacological Sciences Figure 1. Dual role of b-arrestins in GPCR-mediated slow synaptic transmission. (a) The stimulation of dopamine (DA) receptors (DARs) leads to an initial change in receptorconformation that mediates the activation of G proteins, leading to activation (Gas) or inhibition (Gai/o) of adenylyl cyclase and modulation of cAMP-dependent PKA(canonical G-protein-dependent signaling). Receptor phosphorylation by GRKs and the recruitment of b-arrestins then ensue. The recruitment of b-arrestins to receptorsresults in two distinct processes: the termination of G-protein-dependent signaling and the formation of an internalization complex comprising b-arrestin 1 and/or b-arrestin2, adaptor protein 2 (AP2), clathrin and other intermediates. Formation of the internalization complex leads to receptor internalization through clathrin-mediatedendocytosis. The recruitment of b-arrestin 2 following the activation of D2-class receptors also results in the formation of a signaling complex that comprises at least b-arrestin 2, PP2A and Akt. The formation of this complex results in the deactivation of Akt by PP2A and the subsequent stimulation of GSK-3-mediated signaling. (b) Thedifferent kinetics of G-protein-mediated and b-arrestin-2-mediated dopamine receptor signaling following the administration of amphetamine. Shown are the two waves ofsignaling responses involved in slow dopamine synaptic transmission. In the first wave of responses, G-protein-mediated signaling induces a rapid and transient change inthe phosphorylation of direct or indirect PKA targets such as DARPP-32, cAMP-response-element-binding protein (CREB) and ERK. In parallel to these events, a second waveof signaling, mediated by the Akt–b-arrestin-2–PP2A complex, results in a more progressive and longer-lasting response.
leads to the arrestin-dependent internalization of receptors, to three classes: GRK1-like, GRK2-like and GRK4-like principally in clathrin-coated pits (a).
. Whereas GRK1 (rhodopsin kinase) and GRK7 (iodop- Although arrestins were originally identified as key mol- sin kinase) are found primarily in the retina and are ecules that control GPCR desensitization, recent evidence involved in the termination of phototransduction by opsins, indicates that arrestins and, potentially, GRKs also promote GRK2, GRK3, GRK4, GRK5 and GRK6 are widely novel G-protein-independent signaling events that, in expressed in the body, including the brain. Thus, mice the case of dopamine receptors, do not involve a regulation deficient in GRK3 (Adrbk2) GRK4 (Gprk21) , of cAMP-mediated signaling GRK5 (Gprk5) or GRK6 (Gprk6) have beenexamined for their behavioral responses to dopaminergic Role of GRKs in the regulation of dopamine functions drugs. Mice that lack GRKs are normal in most tests {with Studies of dopamine receptor function in mice lacking the exception of the embryonically lethal GRK2 (Adrbk1)- different GRKs have, in most cases, supported a role for knockout mice until challenged with an appropriate these kinases in both GPCR desensitization and signaling agonist Because the GRK–b-arrestin system has dual The seven GRKs in mammals (GRK1–GRK7) belong roles, both suppressing G-protein-mediated signaling and TRENDS in Pharmacological Sciences Box 1. Akt and GSK-3 signaling hydrobromide] . Thus, although it seems unlikely that Akt is a serine/threonine kinase that is regulated through phospha- GRK3 is directly involved in the desensitization of dopamine tidylinositol-3-kinase-mediated signaling . The regulation of Akt receptors, it is possible that this kinase is involved in has been associated with the action of insulin, insulin-related G-protein-independent dopamine receptor signaling.
peptides [e.g. insulin-like growth factor (IGF)] and neurotrophins[e.g. nerve growth factor, brain-derived neurotrophic factor (BDNF)and neurotrophin 3], which exert their biological function by Role of b-arrestin 2 in cAMP-independent dopamine stimulating RTK (see in the main text). The kinases receptor signaling and function GSK-3a and GSK-3b are constitutively active and can be inactivated Several lines of evidence indicate that, in addition to their through the phosphorylation of the single serine residues serine 21 canonical action on G proteins, GPCRs can also activate (GSK-3a) and serine 9 (GSK-3b), which are located in theirregulatory N-terminal domains, by Akt and other kinases . Akt signaling through molecules that are classically involved inhibits GSK-3a and GSK-3b in response to multiple hormones and in the regulation of GPCR desensitization (a).
growth factors, including insulin, IGF and BDNF .
Evidence from heterologous cellular systems demonstratesthat b-arrestins can act as G-protein-independent medi-ators of signaling by scaffolding other proteins such as promoting non-G-protein signaling ), the loss of kinases and their substrates . However, the GRKs can have opposing effects on physiological function: implication of b-arrestin-mediated signaling in biologically either promoting unregulated (supersensitive) receptor relevant processes such as slow synaptic transmission responses because of deficient desensitization or decreas- has remained largely unexplored. Interestingly, both ing responses because of a reduced activation of arrestin- b-arrestin 1 (Arrb1)-knockout and b-arrestin 2 (Arrb2)- mediated non-G-protein signaling pathways.
knockout mice display reduced behavioral responses to In mice that are heterozygous for GRK2 deletion, the dopamine receptor agonist apomorphine Mice locomotor responses to the psychostimulants cocaine and lacking b-arrestin 1 also have a reduced responsiveness to amphetamine or to the direct dopamine receptor agonist cocaine, whereas b-arrestin-2-knockout mice show blunted apomorphine are essentially normal, although certain locomotor responses to the dopamine-dependent actions of doses of cocaine induce slightly enhanced locomotor acti- amphetamine and morphine . Furthermore, in vation Thus, the impact of a partial loss of GRK2 on mice lacking the dopamine transporter [DAT (Slc6a3)- dopamine-receptor-mediated responses seems to be lim- knockout mice], the locomotor hyperactivity phenotype ited, although it is possible that a more pronounced level of associated with enhanced dopaminergic tone can be antag- GRK2 deficiency is necessary to reveal the potential invol- onized by a concomitant lack of b-arrestin 2 . These vement of this kinase in dopamine receptor regulation .
observations indicate that one or many different types of b- Further studies involving brain-specific GRK2-knockout arrestin-containing protein complexes might mediate mice will be necessary to address this issue.
dopamine receptor signaling. We have recently identified GRK6 is the most prominent GRK in the striatum. In one of these mechanisms and shown that b-arrestin 2 is a mice, GRK6 is expressed at high levels in the major striatal signaling intermediate implicated in the cAMP-indepen- neuronal populations, including GABA-containing med- dent regulation of Akt and GSK-3 by dopamine ium spiny neurons and acetylcholine-containing inter- neurons GRK6-knockout mice show significant Investigations of cell signaling in response to persistently supersensitivity to cocaine, amphetamine, morphine and the endogenous ‘trace amine' b-phenylethylamine, which reduction of Akt phosphorylation and activity in the stria- all induce psychomotor activation through the activation of tum of DAT-knockout mice The inactivation of Akt in dopamine neurotransmission Detailed investigations these mice results in concomitant activation of the sub- of these effects revealed that GRK6-knockout mice have an strates GSK-3a and GSK-3b which are inhibited by enhanced coupling of striatal D2-like receptors to G Akt (Further characterization of these signaling proteins, an increased affinity of D2, but not D1, receptors responses using dopamine depletion or dopamine and enhanced locomotor responses to direct dopamine receptor antagonists in DAT-knockout mice showed that receptor agonists . Overall, these observations demon- Akt, GSK-3a and GSK-3b are regulated by D2-class recep- strate that cAMP-mediated signaling by postsynaptic D2- tors ). Furthermore, the D2-class receptor class receptors in the striatum is regulated by GRK6 and antagonist and antipsychotic haloperidol leads to enhanced that D2 receptor desensitization is reduced in the absence Akt phosphorylation and to GSK-3 inhibition in non-trans- genic animals Administration of amphetamine or the Finally, locomotor responses to cocaine are not altered nonselective dopamine receptor agonist apomorphine to in GRK4-knockout mice, which is consistent with the non-transgenic mice also results in an inhibition of Akt limited expression of GRK4 in the brain . Similarly, activity, thus confirming the regulation of the Akt–GSK-3 there are no differences in the effects of cocaine and apo- pathway by dopamine . Interestingly, the regulation of morphine in GRK5-knockout mice, indicating that GRK5 is this pathway by dopaminergic drugs shows different unlikely to be involved in the regulation of dopamine recep- kinetics compared with those of canonical tors However, GRK3-knockout mice have normal cAMP-mediated events and neither Akt nor GSK- basal locomotor activity but demonstrate significantly 3 is affected by direct modulation of cAMP levels in the reduced locomotor responses to cocaine, apomorphine striatum, indicating that the Akt–GSK-3 pathway is not and the D1 receptor agonist SKF81297 [R-(+)-6-chloro-7, controlled by this second messenger By contrast, when

TRENDS in Pharmacological Sciences Figure 2. Regulation of Akt and GSK-3 by drugs affecting monoamine systems and related signaling events. Behavioral changes in dopaminergic responses have beenreported in Akt1-knockout b-arrestin-2-knockout and GSK-3b heterozygote mice. The GSK-3 inhibitors shown antagonize dopamine-dependent behaviors. Lithium (Li2+) both antagonizes dopamine-associated behaviors and enhances Akt phosphorylation . All other drugs listed are included on the basis of theirreported action on Akt or GSK-3 phosphorylation in the mouse striatum. Blue arrows denote activation, red arrows denote inhibition, black arrows denote effects that canbe either activatory or inhibitory depending on specific substrates. Abbreviations: AAPs, atypical antipsychotics; RTK, receptor tyrosine kinase.
b-arrestin 2 Further investigations of the mechanism amphetamine nor apomorphine reduces Akt phosphoryl- by which b-arrestin 2 regulates Akt in response to dopamine ation Furthermore, mice lacking both b-arrestin 2 showed that inhibitors of protein phosphatase 2A (PP2A) and DAT show no inhibitory action of elevated levels of prevent the inhibition of Akt by dopamine, whereas the extracellular dopamine on Akt phosphorylation, demon- stimulation of D2-class receptors causes the formation of strating that dopamine receptors regulate Akt through a protein complex that comprises at least Akt, b-arrestin 2and PP2A The formation of this complex facilitates thedephosphorylation and deactivation of Akt by PP2A in Box 2. Two modalities of slow synaptic transmission response to dopamine and results in the activation of In cultured fibroblasts, b-arrestin-mediated signaling has a slower onset and a more prolonged duration than does GPCR signaling Likewise, the b-arrestin-2-dependent inhibition of Akt bydopamine in the mouse striatum displays a slower but more b-arrestin-2-knockout mice, multiple lines of evidence persistent effect than do signaling events that are regulated by the support the involvement of the b-arrestin-2–Akt–GSK-3 cAMP–PKA pathway (see in the main text).
pathway in the regulation of dopamine-associated beha- The cAMP-dependent phosphorylation of ERK2 and DARPP-32 viors. For example, GSK-3 inhibitors can reduce locomotor peaks and subsides within the first 30 min after the administration of hyperactivity both in DAT-knockout mice and in amphet- dopaminergic drugs such as amphetamine and cocaine . Bycontrast, the inhibition of Akt by amphetamine develops progres- amine-treated wild-type animals Confirmation of sively during the first 30–60 min of drug action and persists over the these pharmacological observations was also obtained duration of the drug behavioral effect .
using genetically engineered animals. GSK-3b (Gsk3b)- This indicates that the regulation and maintenance of certain knockout mice die during embryogenesis, whereas GSK- dopamine-associated behaviors, in addition to the action of some 3b heterozygote mice develop normally without overt dopaminergic drugs, might depend on two complementary wavesof GPCR signaling responses: a first wave of cAMP-mediated phenotypes . Evaluation of the behavioral actions responses with a rapid onset and a relatively short duration, and a caused by amphetamine revealed that GSK-3b heterozy- second wave of responses characterized by slower onsets and gote mice are less responsive to this drug over a range of longer durations, which are dependent on b-arrestin signaling doses, thus supporting the involvement of GSK-3b in the functions. Moreover, the reduced behavioral responsiveness to development of dopamine-associated behaviors Con- dopaminergic drugs acting on either D1- or D2-class receptorsobserved in b-arrestin-1-knockout and b-arrestin-2-knockout mice versely, transgenic mice that express a ‘constitutively indicates that multiple b-arrestin signaling complexes might active' GSK-3b mutant lacking an inhibitory phosphoryl- also mediate dopamine receptor signaling and, potentially, the ation site develop a locomotor hyperactivity phenotype action of other GPCRs implicated in slow synaptic transmission.
that is reminiscent of DAT-knockout mice . Finally, TRENDS in Pharmacological Sciences mice lacking the Akt isoform Akt1 also show enhanced whereas stimulation of 5-HT1A receptors has the opposite disruption of sensory motor gating (pre-pulse inhibition) by effect This action of atypical antipsycho- amphetamine but not by glutamate NMDA receptor tics and 5-HT drugs indicates that Akt and GSK-3 might antagonists The disruption of sensory motor gating function as signal integrators for dopamine and 5-HT by amphetamine, which has been used as a behavioral transmission, and contribute to the action of drugs on paradigm to model psychosis in rodents, is efficiently these neurotransmitter systems However, in the blocked by antipsychotics such as haloperidol that act on absence of extensive behavioral studies addressing the D2-class receptors. Furthermore, Akt1-knockout mice also function of GSK-3 in the regulation of 5-HT function and show a more pronounced deficit in response to D2-class, but the action of 5-HT drugs, this integrative function remains not D1-class, receptor agonists in cognitive tests associated with prefrontal cortex functions . Therefore, because Akt and GSK-3 have been associated with the action of Akt1 is inhibited following the stimulation of D2-class the mood stabilizer lithium. Lithium is a direct inhibitor of receptors , the altered behavioral effects caused by GSK-3 that can also inhibit the activity of this kinase in amphetamine and D2-class receptor agonists in Akt1- cells through an indirect mechanism (involving knockout mice further support the involvement of Akt Akt activation . Acute and chronic adminis- inhibition in dopamine-mediated behavioral responses.
tration of lithium inhibits brain GSK-3 activity in mice,as revealed by enhanced regulatory N-terminal domain Involvement of Akt and GSK-3 in the action of phosphorylation . Moreover, GSK-3 inhibitors and psychotropic drugs reduced GSK-3b expression both reproduce some of the Typical antipsychotics such as haloperidol are thought to behavioral actions of lithium in rodents, including its exert most of their actions by blocking D2-class receptors, inhibitory action on dopamine-dependent locomotor hyper- thus supporting a role for dopamine neurotransmission in activity . Although the mechanism by which the etiology of schizophrenia. Recent genetic association lithium regulates Akt and GSK-3 activity is unclear, these studies have established a link between a deregulation of observations indicate that a direct or indirect inhibition of Akt signaling and schizophrenia. Following transmission– GSK-3 might contribute to the psychopharmacological disequilibrium tests, a major association of Akt1 haplo- actions of lithium, at least in part, by inhibiting dopamine types with schizophrenia has been reported in several independent cohorts of schizophrenic patients Furthermore, reduced Akt activity or expression levels Future perspectives were also shown in the brains of schizophrenic patients The characterization of the mechanisms by which b-arrestins and GRKs contribute to dopamine receptor Thus, because stimulation of striatal D2-class receptors signaling is at an early stage and it would be naı¨ve to by dopamine results in an inhibition of Akt it is believe that the complete palette of molecular responses possible that a partial loss of function of Akt1 in schizo- associated with these molecules has been identified. Of phrenia results in exacerbated responses to D2 receptor particular interest, the further characterization of GRKs stimulation that are similar to those observed in Akt1- and other modulators of b-arrestins in the dopamine sys- knockout mice. In the same way, classical antipsychotics tem might enable researchers to determine the functions of could correct this imbalance by preventing further these molecules in regulating the positive and negative reductions of Akt activity by D2-class receptors ( actions of b-arrestins on dopamine receptor signaling. Also In addition, so-called atypical antipsychotics have of interest, the D2-receptor-interacting protein spinophilin recently been shown to either activate Akt or mimic has been shown to interfere with b-arrestin functions Akt activity by increasing the phosphorylation of its sub- by competing with GRK2 for GPCR binding , and GRK2 strates GSK-3a and GSK-3b Atypical antipsychotics has been shown to regulate Akt in non-neuronal cells can be distinguished functionally from typical antipsycho- indicating a potential role of these molecules in the regu- tics by their reduced affinity and lower specificity for D2 lation of b-arrestin-mediated D2-class receptor signaling.
receptors. Many atypical antipsychotics display a strong Furthermore, although behavioral studies indicate that affinity for 5-hydroxytryptamine (5-HT)2A receptors .
b-arrestin 1 also has signaling functions in dopamine The atypical antipsychotic clozapine enhances Akt–GSK-3 neurotransmission the molecular mechanism(s) of signaling in cell culture systems Acute or chronic in these functions has yet to be identified. Interestingly, b- vivo administration of multiple atypical antipsychotics – arrestin 1 has recently been shown to function as a nuclear including risperidone, olanzapine, clozapine, quetiapine signaling molecule that regulates chromatin structure and and ziprasidone – results in an inhibition of GSK-3b in gene expression in cultured fibroblasts . Such different brain regions Furthermore, drugs that changes in chromatin organization have also been affect 5-HT neurotransmission, such as selective 5-HT- suggested to participate in the development of long-term reuptake inhibitors, monoamine oxidase inhibitors and adaptation and addiction to dopaminergic drugs such as tricyclic antidepressants, amplify the action of atypical cocaine thus raising the possibility that b-arrestin 1 antipsychotics on GSK-3b Interestingly, increases has a role in this phenomenon. Finally, the identification of in GSK-3 activity were recently reported in the prefrontal a cAMP-independent (b-arrestin-dependent) modality of cortex of depressed suicide victims . Two 5-HT recep- dopamine receptor signaling that involves the Akt–GSK-3 tors seem to have antagonistic roles in regulating GSK-3b: cascade indicates that dopamine receptor functions are stimulation of 5-HT2A receptors leads to kinase activation, mediated by multiple mechanisms that collaborate to TRENDS in Pharmacological Sciences fine-tune the expression of dopaminergic responses under 21 Peppel, K. et al. (1997) G protein-coupled receptor kinase 3 (GRK3) different physiological and environmental conditions.
gene disruption leads to loss of odorant receptor desensitization. J.
Biol. Chem. 272, 25425–25428 These mechanisms could be crucial for regulating the 22 Gainetdinov, R.R. et al. (1999) Muscarinic supersensitivity and expression of distinct dopamine-associated behaviors impaired receptor desensitization in G protein-coupled receptor and/or for ensuring the robustness of important phys- kinase 5-deficient mice. Neuron 24, 1029–1036 iological outcomes. Understanding the complexity of this 23 Gainetdinov, R.R. et al. (2003) Dopaminergic supersensitivity in G interplay between these modalities of dopamine receptor protein-coupled receptor kinase 6-deficient mice. Neuron 38, 291–303 signaling could enable the development of novel pharma- 24 Jaber, M. et al. (1996) Essential role of b-adrenergic receptor kinase 1 cological treatments with improved therapeutic actions in cardiac development and function. Proc. Natl. Acad. Sci. U. S. A. 93, while avoiding undesired side-effects.
25 Lefkowitz, R.J. and Shenoy, S.K. (2005) Transduction of receptor signals by b-arrestins. Science 308, 512–517 This work was supported in part by National Institutes of Health grants 26 Bohn, L.M. et al. (2003) Enhanced rewarding properties of morphine, DA-13511, NS-19576, MH-73853 and MH-40159 (to M.G.C.). M.G.C. is but not cocaine, in b-arrestin-2 knock-out mice. J. Neurosci. 23, 10265– the Lattner Foundation National Alliance for Research on Schizophrenia and Depression (NARSAD) Distinguished Investigator. J-M.B. is the 27 Sotnikova, T.D. et al. (2005) Dopamine-independent locomotor actions NARSAD Southwest Florida Investigator and the recipient of a of amphetamines in a novel acute mouse model of Parkinson disease.
fellowship from the Canadian Institutes of Health Research.
PLoS Biol. 3, e271 28 Emamian, E.S. et al. (2004) Convergent evidence for impaired AKT1–GSK3b signaling in schizophrenia. Nat. Genet. 36, 131– 1 Missale, C. et al. (1998) Dopamine receptors: from structure to function.
Physiol. Rev. 78, 189–225 29 Gould, T.D. et al. (2004) AR-A014418, a selective GSK-3 inhibitor, 2 Greengard, P. (2001) The neurobiology of slow synaptic transmission.
produces antidepressant-like effects in the forced swim test. Int. J.
Science 294, 1024–1030 Neuropsychopharmacol. 7, 387–390 3 Carlsson, A. (2001) A paradigm shift in brain research. Science 294, 30 Hoeflich, K.P. et al. (2000) Requirement for glycogen synthase kinase- 3b in cell survival and NF-kB activation. Nature 406, 86–90 4 Gainetdinov, R.R. et al. (2002) Monoamine transporter pharmacology 31 Prickaerts, J. et al. (2006) Transgenic mice overexpressing glycogen and mutant mice. Trends Pharmacol. Sci. 23, 367–373 synthase kinase 3b: a putative model of hyperactivity and mania. J.
5 Heimer, L. et al. (1995) Basal ganglia, In The Rat Nervous System Neurosci. 26, 9022–9029 (2nd edn) (Paxinos, G., ed.), pp. 579–629, Academic Press 32 Lai, W.S. et al. (2006) Akt1 deficiency affects neuronal morphology and 6 Valjent, E. et al. (2006) Role of the ERK pathway in psychostimulant- predisposes to abnormalities in prefrontal cortex functioning. Proc.
induced locomotor sensitization. BMC Neurosci. 7, 20 Natl. Acad. Sci. U. S. A. 103, 16906–16911 7 Valjent, E. et al. (2005) Regulation of a protein phosphatase cascade 33 Bajestan, S.N. et al. (2006) Association of AKT1 haplotype with the risk allows convergent dopamine and glutamate signals to activate ERK in of schizophrenia in Iranian population. Am. J. Med. Genet. B.
the striatum. Proc. Natl. Acad. Sci. U. S. A. 102, 491–496 Neuropsychiatr. Genet. 141, 383–386 8 Beaulieu, J.M. et al. (2006) Paradoxical striatal cellular signaling 34 Schwab, S.G. et al. (2005) Further evidence for association of variants responses to psychostimulants in hyperactive mice. J. Biol. Chem.
in the AKT1 gene with schizophrenia in a sample of European sib-pair 281, 32072–32080 families. Biol. Psychiatry 58, 446–450 9 Beaulieu, J.M. et al. (2005) An Akt/b-arrestin 2/PP2A signaling 35 Ikeda, M. et al. (2004) Association of AKT1 with schizophrenia complex mediates dopaminergic neurotransmission and behavior.
confirmed in a Japanese population. Biol. Psychiatry 56, 698–700 Cell 122, 261–273 36 Zhao, Z. et al. (2006) Insulin receptor deficits in schizophrenia and in 10 Beaulieu, J.M. et al. (2004) Lithium antagonizes dopamine-dependent cellular and animal models of insulin receptor dysfunction. Schizophr.
behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci. U. S. A. 101, 5099–5104 37 Kang, U.G. et al. (2004) The effects of clozapine on the GSK-3-mediated 11 Arriza, J.L. et al. (1992) The G-protein-coupled receptor kinases signaling pathway. FEBS Lett. 560, 115–119 bARK1 and bARK2 are widely distributed at synapses in rat brain.
38 Li, X. et al. (2007) Regulation of mouse brain glycogen synthase J. Neurosci. 12, 4045–4055 kinase-3 by atypical antipsychotics. Int. J. Neuropsychopharmacol.
12 Benovic, J.L. et al. (1991) Cloning, expression, and chromosomal localization of b-adrenergic receptor kinase 2. A new member of the 39 Kapur, S. and Remington, G. (2001) Atypical antipsychotics: new receptor kinase family. J. Biol. Chem. 266, 14939–14946 directions and new challenges in the treatment of schizophrenia.
13 Gainetdinov, R.R. et al. (2004) Desensitization of G protein-coupled Annu. Rev. Med. 52, 503–517 receptors and neuronal functions. Annu. Rev. Neurosci. 27, 107–144 40 Alimohamad, H. et al. (2005) Antipsychotics alter the protein 14 Shenoy, S.K. and Lefkowitz, R.J. (2003) Multifaceted roles of b- expression levels of b-catenin and GSK-3 in the rat medial arrestins in the regulation of seven-membrane-spanning receptor prefrontal cortex and striatum. Biol. Psychiatry 57, 533–542 trafficking and signalling. Biochem. J. 375, 503–515 41 Karege, F. et al. (2007) Alteration in kinase activity but not in protein 15 Lohse, M.J. et al. (1990) b-Arrestin: a protein that regulates b- levels of protein kinase B and glycogen synthase kinase-3b in ventral adrenergic receptor function. Science 248, 1547–1550 prefrontal cortex of depressed suicide victims. Biol. Psychiatry 61, 240– 16 Ferguson, S.S. et al. (1996) Role of b-arrestin in mediating agonist- promoted G protein-coupled receptor internalization. Science 271, 363– 42 Li, X. et al. (2004) In vivo regulation of glycogen synthase kinase-3b (GSK3b) by serotonergic activity in mouse brain. Neuropsychophar- 17 Laporte, S.A. et al. (2002) b-Arrestin/AP-2 interaction in G protein- macology 29, 1426–1431 coupled receptor internalization: identification of a b-arrestin binging 43 Beaulieu, J.M. (2007) Not only lithium: regulation of glycogen synthase site in b2-adaptin. J. Biol. Chem. 277, 9247–9254 18 Luttrell, L.M. et al. (2001) Activation and targeting of extracellular Neuropsychopharmacol. 10, 3–6 signal-regulated kinases by b-arrestin scaffolds. Proc. Natl. Acad. Sci.
44 Chalecka-Franaszek, E. and Chuang, D.M. (1999) Lithium activates U. S. A. 98, 2449–2454 the serine/threonine kinase Akt-1 and suppresses glutamate-induced 19 Beaulieu, J.M. and Caron, M.G. (2005) b-Arrestin goes nuclear. Cell inhibition of Akt-1 activity in neurons. Proc. Natl. Acad. Sci. U. S. A. 96, 20 Shenoy, S.K. et al. (2006) b-Arrestin-dependent, G protein-independent 45 Zhang, F. et al. (2003) Inhibitory phosphorylation of glycogen synthase ERK1/2 activation by the b2 adrenergic receptor. J. Biol. Chem. 281, kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J. Biol. Chem. 278, 33067–33077 TRENDS in Pharmacological Sciences 46 Klein, P.S. and Melton, D.A. (1996) A molecular mechanism for the 54 Chao, J. and Nestler, E.J. (2004) Molecular neurobiology of drug effect of lithium on development. Proc. Natl. Acad. Sci. U. S. A. 93, addiction. Annu. Rev. Med. 55, 113–132 55 Stelling, J. et al. (2004) Robustness of cellular functions. Cell 118, 675– 47 Phiel, C.J. and Klein, P.S. (2001) Molecular targets of lithium action.
Annu. Rev. Pharmacol. Toxicol. 41, 789–813 56 Scheid, M.P. and Woodgett, J.R. (2001) PKB/AKT: functional 48 De Sarno, P. et al. (2002) Regulation of Akt and glycogen synthase insights from genetic models. Nat. Rev. Mol. Cell Biol. 2, 760– Neuropharmacology 43, 1158–1164 57 Chen, M.J. and Russo-Neustadt, A.A. (2005) Exercise activates the phosphatidylinositol 3-kinase pathway. Brain Res. Mol. Brain Res.
haploinsufficiency mimics the behavioral and molecular effects of lithium. J. Neurosci. 24, 6791–6798 58 Frame, S. and Cohen, P. (2001) GSK3 takes centre stage more than 20 50 Smith, F.D. et al. (1999) Association of the D2 dopamine receptor third years after its discovery. Biochem. J. 359, 1–16 cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting 59 Ahn, S. et al. (2004) Differential kinetic and spatial patterns of b- protein. J. Biol. Chem. 274, 19894–19900 arrestin and G protein-mediated ERK activation by the angiotensin II 51 Wang, Q. et al. (2004) Spinophilin blocks arrestin actions in vitro and in receptor. J. Biol. Chem. 279, 35518–35525 vivo at G protein-coupled receptors. Science 304, 1940–1944 60 Valjent, E. et al. (2000) Involvement of the extracellular signal- 52 Liu, S. et al. (2005) A crucial role for GRK2 in regulation of endothelial regulated kinase cascade for cocaine-rewarding properties. J.
cell nitric oxide synthase function in portal hypertension. Nat. Med. 11, Neurosci. 20, 8701–8709 61 Svenningsson, P. et al. (2003) Diverse psychotomimetics act through a 53 Kang, J. et al. (2005) A nuclear function of b-arrestin 1 in GPCR common signaling pathway. Science 302, 1412–1415 signaling: regulation of histone acetylation and gene transcription.
62 Beaulieu, J.M. et al. (2007) Regulation of Akt signaling by D2 and D3 Cell 123, 833–847 dopamine receptors in vivo. J. Neurosci. 27, 881–885 – linking scientists to new research and thinking Designed for scientists' information needs, is powered by the latest technology with customer-focused navigation and an intuitive architecture for an improved user experience and The easy-to-use navigational tools and structure connect scientists with vital information – all from one entry point. Users can perform rapid and precise searches with our advanced search functionality, using the FAST technology of, the free science search engine. Users can define their searches by any number of criteria to pinpoint information and resources. Search by a specific author or editor, book publication date, subject area – life sciences, health sciences, physical sciences and social sciences – or by product type. Elsevier's portfolio includes more than 1800 Elsevier journals, 2200 new books every year and a range of innovative electronic products.
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Pii: s0378-7753(02)00194-5

Journal of Power Sources 110 (2002) 321–329 Battery performance models in ADVISOR National Renewable Energy Laboratory, Golden, CO 80401, USA This paper summarizes battery modeling capabilities in ADVISOR—the National Renewable Energy Laboratory's advanced vehicle simulator written in the Matlab/Simulink environment. ADVISOR's Matlab-oriented battery models consist of the following: (1) an internalresistance model, (2) a resistance–capacitance (RC) model, (3) a PNGV capacitance model, (4) a neural network (nnet) lead acid model, and(5) a fundamental lead acid battery model. For the models, the electric schematics (where applicable), thermal models, accuracy, existingdatasets, and sample validation plots are presented. A brief summary of ADVISOR's capabilities for co-simulation with Saber is presented,which links ADVISOR with Saber's lead acid battery model. The models outlined in this paper were presented at the workshop on‘Development of Advanced Battery Engineering Models' in August 2001.# 2002 Elsevier Science B.V. All rights reserved.

Protocolo Nacional Unificado para la Protección y Asistencia Integral a Personas Víctimas de Trata Protocolo Nacional Unificado para la Protección y Asistencia Integral a Personas Víctimas de Trata PROTOCOLO NACIONAL UNIFICADO PARA LA PROTECCIÓN Y ASISTENCIA INTEGRAL A PERSONAS VÍCTIMAS DE TRATA Jefe de Misión OIM EcuadorRogelio Bernal Equipo del Programa Contra la Trata de Personas OIMArgentina SantacruzBelén Rodríguez