Comments on Related News
Related News: Dopamine Receptors: The Right Combination Unlocks Calcium ReleaseComment by: Christoph Kellendonk
Submitted 29 January 2007
Posted 30 January 2007
I recommend the Primary Papers
The paper by Rashid et al. presents yet another interesting example of how dopamine D2 receptors may activate signaling pathways independent of the classical cAMP pathway, a finding that may have potential therapeutic implications. Most antipsychotic drugs that ameliorate positive symptoms antagonize D2 receptors, which may be also at the origin of many of the side effects associated with these medications. But, if antipsychotic action utilizes signaling pathways that are distinct from those responsible for the side effects we may have the chance to develop new compounds with higher specificity and reduced side effects. Observations such as those made in Rashid et al. are essential steps in this direction.
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Related News: Dopamine Receptors: The Right Combination Unlocks Calcium Release
Comment by: Eleanor Simpson
Submitted 29 January 2007
Posted 30 January 2007
I recommend the Primary Papers
This is a very exciting paper. The concept of D1 and D2 cellular coexpression had been debated for a long time; with limited antibodies for these receptors available, investigators had found conflicting results, dependent on the method of detection used.
The authors recently described the existence of D1-D2
hetero-oligomers. Here they elucidate a possible function of such a complex. The authors begin with a very thorough biochemical characterization in HEK cells stably expressing either D1, D2, or both receptors, concluding that SKF83959 is a specific agonist for Gq/11 coupled D1-D2 receptor hetero-oligomers. By using striatal membrane preparations from wild-type, D1 mutant, or D2 mutant mice, the authors identify a D1-D2 Gq11 complex in the brains of mature mice.
The authors conclude by suggesting that D1-D2 receptor signaling may be altered in neuropsychiatric disease and that this should be explored. This may be a little premature, and perhaps some more fundamental characterization of this newly discovered complex should first be undertaken. The increase in GTPgS incorporation by 100 uM dopamine is modest compared to the increase observed with 100 uM SKF+Quin treatment. Since none of these experiments are under in vivo physiological conditions, it would be reassuring to see that this modest DA response is also blocked by SCH or RAC.
The fact that the D1-D2 Gq/11 complex was detected in 8-month-old mice but not 3-month-old mice is fascinating and begs the questions, when do these complexes form? How and why do they form? Both RT-PCR and primary culture experiments suggest that at least a fraction of neurons in the striatum coexpress D1 and D2 receptors in young adult mice. Does the number of coexpressing neurons increase with age? Or does hetero-oligomer coupling to Gq/11 increase with age? There is evidence that D1 receptor-Gs protein coupling is reduced in very old rats (Sugawa et al., 1996). Is the appearance of D1-D2 Gq/11 complexes in the striatum relevant to brain maturation, or does it relate to a decline in DA signaling efficiency?
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Related News: An Arrestin Development: Antipsychotic Drugs Hit Dopamine Signaling in New Way
Comment by: Zachary Z. Freyberg, Eneko Urizar, Holly Moore, Jeffrey Lieberman (SRF Advisor), Jonathan Javitch
Submitted 30 December 2008
Posted 30 December 2008
Reevaluation of the dopamine D2 receptor in the treatment of schizophrenia: Novel intracellular mechanisms as predictors of antipsychotic efficacy
Since the advent of antipsychotic medications, there have been many speculations about their precise mechanisms of therapeutic action. Although it is apparent that blockade of dopamine D2 receptors (D2R) is crucial to the efficacy of all current antipsychotic medications, it is not clear which signaling events downstream of the D2R must be blocked for the therapeutic actions of antipsychotics and which events, when blocked, lead instead to side effects.
The best characterized D2R-mediated signaling pathways involve coupling of the receptor to pertussis toxin-sensitive G proteins of the Gi and Go subfamilies (Sidhu and Niznik, 2000), through which D2R activation results in a decrease in cyclic AMP (cAMP). D2R activation can also have a number of other effects, including enhancement of specific potassium currents, inhibition of L-type calcium currents, mediation of extracellular signal-regulated kinase 1 (ERK1) and potentiation of arachidonic acid release (Beom et al., 2004; Missale et al., 1998; Perez et al., 2006; Hernández-López et al., 2000). There is growing evidence that D2Rs can interact with a number of membrane-bound or intracellular proteins, which may further modulate signaling specificity (reviewed in Terrillon and Bouvier, 2004; Ferré et al., 2007a). In particular, D2R heteromerization may result in a switch from Gi/o coupling to Gs (i.e., through D2R and cannabinoid 1 receptor interaction) (Kearn et al., 2005) or to coupling with Gq (as suggested in D2R and D1R interactions) (Rashid et al., 2007). Moreover, heteromerization between D2R and other receptors such as the adenosine A2A receptor may allow for reciprocal modulation of D2R function (Ferré et al., 2007a; Ferré et al., 2007b). It also has been suggested that calcium signaling mechanisms may modulate D2R’s signaling efficacy; interaction between D2R and calcium-binding protein S100B results in enhanced D2R intracellular signaling (Liu et al., 2008; Stanwood, 2008).
The interaction between D2R and arrestin has received increasing attention. Following D2R activation, D2R signaling is attenuated by recruitment of arrestin 3 to the cell surface where it binds to the receptor (Klewe et al., 2008; Lan et al., 2008a ; Lan et al., 2008b), leading to inactivation and internalization of the D2R. Arrestin 3 also binds Akt—a serine/threonine kinase involved in multiple cellular functions and implicated clinically in schizophrenia (Arguello and Gogos; 2008; Beaulieu et al., 2005; Brazil and Hemmings, 2001; Brazil et al., 2004; Emamian et al., 2004; Kalkman, 2006). Following D2R activation by dopamine, the signaling scaffold formed by arrestin 3, while facilitating receptor desensitization and internalization, also recruits Akt into a complex with the phosphatase PP2A, which dephosphorylates and consequently inactivates Akt (Beaulieu et al., 2007a ). Thus, D2R activation inhibits Akt activity through an arrestin-dependent but G protein-independent pathway (Beaulieu et al., 2007a ; Beaulieu et al., 2007b). Curiously, the mood stabilizer, lithium, has been shown to disrupt the arrestin 3-Akt-PP2A complex, thereby preventing dopamine-induced dephosphorylation of Akt and blocking amphetamine-induced locomotion (Beaulieu et al., 2008). Moreover, amphetamine-induced locomotion is greatly diminished in arrestin 3 knockout mice, suggesting that this pathway is critical to at least some psychostimulant effects (Beaulieu et al., 2005).
Using newly developed BRET (bioluminescent resonance energy transfer) biosensors in assays that measure direct protein-protein interactions within the living cell, recent studies have demonstrated that antipsychotic medications prevent arrestin 3 recruitment by blocking D2R activation (Klewe et al., 2008; Masri et al., 2008). Masri et al. (2008) hypothesized that antipsychotic drugs achieve their therapeutic effect through a common mechanism involving blockade of arrestin-mediated signaling (Masri et al., 2008). Masri et al. (2008) also demonstrated that nearly all antipsychotics tested (including haloperidol, clozapine, olanzapine, desmethylclozapine, chlorpromazine, quetiapine, risperidone and ziprasidone) behave as inverse agonists to decrease constitutive G protein signaling as well as to prevent the agonist quinpirole from inhibiting cAMP synthesis (via D2R-mediated Gi/o signaling). The lone exception, aripiprazole, behaved as a partial agonist instead of as an inverse agonist of the G protein mediated effects. The latter finding is consistent with previous studies highlighting aripiprazole’s ability to differentially modulate various G protein-mediated effector pathways, a property termed “functional selectivity” (Mailman, 2007; Urban et al., 2007). Using the BRET assay, Klewe et al. (2008) and more recently Masri et al. (2008) demonstrated that all antipsychotics, including aripiprazole, block arrestin 3 recruitment. This finding has led Masri et al. (2008) to suggest that blockade of arrestin 3 recruitment to the D2R, and not modulation of G-protein-mediated pathways, is a common and specific property of all current antipsychotics and may be used to predict the antipsychotic efficacy of drugs in development (Masri et al., 2008). This hypothesis remains to be tested and at present appears to lean heavily on the evidence for aripiprazole’s atypical effects on constitutive (non-agonist-dependent) D2R-mediated G-protein signaling. Indeed, the fact that lithium acts to prevent arrestin-mediated signaling in response to amphetamine but is not an effective antipsychotic in monotherapy suggests that antipsychotic action may be more complex than simple blockade of D2R-mediated arrestin signaling. In addition, the ability of antipsychotics, including aripiprazole, to block agonist binding to the D2R and thus activation of the receptor, makes it likely that agonist-induced activity in multiple signaling pathways will also be blocked by these drugs.
Despite the paucity of direct evidence for D2R-arrestin coupling as the mechanism underlying the antipsychotic effects of drugs, the hypothesis remains quite intriguing Given that Akt and its downstream target GSK-3 (glycogen synthase kinase-3) have been implicated in schizophrenia in a number of genetic and postmortem studies, and the Akt/GSK-3 pathway might represent an opening into alternative therapeutics of schizophrenia. Akt is a serine/threonine kinase that may have significant roles in synaptic physiology and neurodegeneration (Brazil et al., 2004). Recruited to the cell surface by binding to phosphatidylinositol 3,4,5 trisphosphate, Akt is activated via phosphorylation of 3-phosphoinoitide-dependent protein kinase 1 (PDK1) and the rictor-mTOR complex (Brazil and Hemmings, 2001; Sarbassov et al., 2005). Once active, Akt phosphorylates GSK-3, thereby inactivating it. Since D2R activation leads to inactivation of Akt, this also results in increased GSK-3 activity (Beaulieu et al., 2004; Lovestone et al., 2007). GSK-3 activity also plays an important role in modulating the dopaminergic response to amphetamine. Amphetamine’s stimulation of DAT-mediated dopamine efflux and subsequent D2R stimulation likely results in Akt inactivation and increased GSK-3 activity. Rats treated with the specific GSK-3 inhibitor, AR-A014418, failed to display amphetamine-induced hyperactivity (Gould et al., 2004). Similarly, heterozygous GSK-3β knockout mice (expressing approximately half of wildtype levels of GSK-3β) displayed significantly reduced levels of locomotor activity following amphetamine treatment (Beaulieu et al., 2004). Additionally, treatment of dopamine transporter (DAT) knockout mice with multiple GSK-3 inhibitory drugs inhibited the ordinarily hyperactive behavior of the non-treated DAT knockout mice (Beaulieu et al., 2004).
In a mouse model, acute and chronic haloperidol treatment was shown to increase levels of active, phosphorylated Akt isoform Akt1 and increased phosphorylation and inactivation of GSK-3β (Emamian et al., 2004). Thus, it was suggested that haloperidol treatment may compensate for the decreased levels of endogenous Akt1 in the frontal cortex of people with schizophrenia (Emamian et al., 2004). Atypical antipsychotics also impact on the regulation of Akt and GSK-3β activities. For example, treatment with clozapine results in increased levels of phosphorylated GSK-3β (Kang et al., 2004; Sutton et al., 2007). Interestingly, however, differences between haloperidol and atypical antipsychotics have emerged in the kinetics of Akt/GSK-3 phosphorylation, the levels of proteins expressed following drug exposure, and the signaling pathways that are preferentially activated (Roh et al., 2007).
The abilities of antipsychotic drugs to activate distinct signaling pathways to mediate their ostensible differential pharmacologic effects would suggest clinical variation in their therapeutic effects. However, meaningful differences in the clinical effects of these compounds have not been clearly or consistently evident. The initial reports of superior efficacy of the so-called second generation or atypical antipsychotics on measures of psychosis (Kane et al., 1988), negative symptoms (Tollefson et al., 1997), cognitive deficits (Keefe et al., 1999), relapse prevention (Csernansky et al., 2002), adherence (Wahlbeck et al., 2001) and illness progression (Lieberman et al., 2005a), have not been borne out by more recent studies (Geddes et al., 2000; Lieberman et al., 2005b; Jones et al., 2006; Leucht et al., 2008). Indeed, the differences between antipsychotic drugs are most evident in the types, frequency and severity of side effects rather than in their therapeutic actions (Leucht et al., 1999; Allison et al., 1999; Henderson et al., 2005). In this regard the emerging pattern of variation in the molecular mechanisms of antipsychotic drugs in the face of their common clinical profiles resembles what was previously observed with the variability in neuroreceptor binding profiles (Kinon and Lieberman, 1996). The marked differences in the affinities and selectivity of the various antipsychotics for the receptors of different neurotransmitters were thought to underlie a rich pattern of clinical variation in the therapeutic actions of this group of drugs (Miyamoto et al., 2005). However, this hypothesis has not been supported by clinical studies (Lieberman, 2006; Lewis and Lieberman, 2008).
Nevertheless, there is reason to be hopeful that through functional selectivity, or other potential actions, the abilities of drugs to engage different signaling pathways will confer novel therapeutic effects that will improve the efficacy of treatments. In this context, the studies of Masri et al. (2008) and Klewe et al. (2008) highlight the plausibility that D2R/arrestin 3 modulation of Akt and GSK-3 activity is an important mechanism underlying psychosis and a potential target for future antipsychotic drugs. Further study of this pathway, including studies designed to reverse the effects of D2R antagonists or partial agonists (antipsychotic drugs) with systematic differential manipulation of the signaling pathways induced by D2R activation, is likely to be a fruitful path toward the development of novel treatments for schizophrenia-related disorders.
Acknowledgements: The authors would like to acknowledge the generous support of the Lieber Center for Schizophrenia Research at Columbia University
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Related News: Coupling Between D1 and D2 Receptors Implicated in Depression
Comment by: Christoph Kellendonk
Submitted 14 December 2010
Posted 14 December 2010
Heterodimerization between D1 and D2 receptors is a recently discovered, novel mechanism by which D1 and D2 receptors activate Gq-mediated signaling in the brain. Although first met with skepticism, evidence for the existence of functional D1/D2 heterodimers under physiological conditions has become more and more convincing.
Heterodimerization between D1 and D2 receptors is linked to their coexpression in the same cell. The localization of D1 and D2 receptors has been extensively studied in the striatum. After D1 and D2 receptors were cloned 20 years ago, in situ hybridization studies suggested that there are two main populations of neurons in the striatum: one population that predominantly expresses D1 receptors and projects mono-synaptically to the substantia nigra (called the striato-nigral or direct pathway), and the other population that expresses D2 receptors and projects over several synapses to the substantia nigra (called the striato-pallidal or indirect pathway).
When these studies were followed up using single cell PCR and immunohistochemistry (IHC) using antibodies against D1 and D2 receptors, the percentage of neurons coexpressing both receptors increased to 15-30 percent, or even 100 percent for some IHC studies. One argument for the inconsistency between the early in situ hybridization studies and the newer studies had been that in situ hybridization may not be as sensitive as single cell PCR or IHC. However, the main problem with IHC is that different antibodies were used in different studies, and it is known that not all available antibodies against D2 receptors are really specific.
Recently, mice that express green fluorescent protein under the control of either the D1 or the D2 promoter have been developed that allow for selective labeling of D1- and D2-positive MSNs, respectively. The findings with D1- and D2-GFP mice are more in line with the original in situ hybridization studies showing relatively low overlap of expression in the dorsal striatum (5-7 percent of MSNs) and higher overlap in the ventral striatum (around 20 percent).
The problem of antibody specificity has also been a problem for studying heterodimers in the striatum. Therefore, in a recent study, Susan George's laboratory at the University of Toronto took great effort in testing the specificity of their antibodies (Perreault et al., 2010). One important control they included was knockout mice in which the D1 or the D2 receptor gene was inactivated. Immunohistochemistry for D1 and D2 did not show any signal in these mice, indicating specificity of the employed antibodies. Moreover, colocalization studies with these antibodies showed a degree of overlap that was comparable to what had been observed in the classical in situ hybridization studies and the recent studies using D1- and D2-GFP mice. Last, the authors used FRET technology and demonstrated coexpression at a spatial resolution that supports a direct interaction between both receptors in vivo.
The laboratory of Fang Liu, also at the University of Toronto, has now found that heterodimerization may be increased under pathological conditions. Using immunoprecipitation experiments, Pei et al. found increased coupling between D1Rs and D2Rs in the striatum and the cortex of patients with major depression (Pei et al., 2010). Perreault et al. found increased affinity for SKF83959, a heterodimer specific dopamine receptor agonist in the globus pallidus of patients with schizophrenia (Perreault et al., 2010). Since the globus pallidus is the main output structure of the indirect pathway of the striatum, it raises the question whether the degree of D1 and D2 receptor coexpression may be increased under pathological conditions
Obviously, both postmortem findings will need replication using higher subject numbers. Due to the confounding effects of postmortem tissue analysis and medication, PET imaging studies could greatly benefit this analysis. Imaging could be done earlier in the disease process and under drug-naïve conditions. The challenge here may be the development of appropriate tracers that are both suitable for PET imaging and specific for detecting heterodimers.
That SKF83959 selectively activates heterodimers raises the possibility for the development of selective antagonists. If increased heterodimers are indeed involved in the pathophysiology of depression and schizophrenia, they may be good targets for treating negative symptoms such as anhedonia and avolition that are associated with both disorders. They may also help against psychosis, though we would then expect that D1 receptor antagonists, which block heterodimer-mediated signaling, would be effective antipsychotics.
Perreault ML, Hasbi A, Alijaniaram M, Fan T, Varghese G, Fletcher PJ, Seeman P, O'Dowd BF, George SR The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: increased high affinity state following amphetamine and in schizophrenia. J Biol Chem 285:36625-36634. Abstract
Pei L, Li S, Wang M, Diwan M, Anisman H, Fletcher PJ, Nobrega JN, Liu F Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects. Nat Med 16:1393-1395. Abstract
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Related News: Coupling Between D1 and D2 Receptors Implicated in Depression
Comment by: Jeremy Seamans
Submitted 23 December 2010
Posted 23 December 2010
Christoph nicely summarized key aspects of the paper in the context
of the relevant literature. In addition, I feel the paper makes an
important contribution because it draws attention to a signaling
mechanism that may help explain some of the more contentious effects
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Related News: NYAS 2011—New Molecular Targets for Schizophrenia
Comment by: Jim Woodgett
Submitted 26 April 2011
Posted 27 April 2011
Several of the reports from the NYAS meeting describe the potential role of GSK-3β in DISC1 functions. This is one of two isoforms, and the other, GSK-3α, tends to get short shrift from researchers. This is problematic for several reasons. Firstly, the two isoforms, despite being derived from distinct genes, are essentially identical within their catalytic domains. Consequently, there are no small molecule inhibitors that that are isoform selective, and the two proteins are highly redundant (albeit not completely) in function. Secondly, in the case of DISC1, there are new data indicating a role for GSK-3α in DISC1 functions. Small molecule (isoform indiscriminate) inhibitors of GSK-3 restore behavioral deficits of DISC1 L100P animals, and this is also achieved by genetic inactivation of one allele of GSK-3α (Lipina et al., 2011). Examination of the brains of the DISC1 and DISC1/GSK-3α+/- animals revealed that dendritic spine density deficits observed in DISC1 L100P brains were restored upon deletion of one copy of GSK-3α (Lee et al., 2011).
From a therapeutic point of view, there appears to be no easy way to selectively inhibit only one isoform of GSK-3 (the only means is via RNA interference), so perhaps it is fortunate that both isoforms appear to play similar roles? Birds, on the other hand, appear to have selectively lost GSK-3α, though the consequences in terms of brain development and function are currently unclear (Alon et al., 2011).
Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. (2011). Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse 65(3):234-48. Abstract
Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. (2011) Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice. Schizophr Res. Abstract
Alon LT, Pietrokovski S, Barkan S, Avrahami L, Kaidanovich-Beilin O, Woodgett JR, Barnea A, Eldar-Finkelman H. (2011) Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation. FEBS Lett. 585(8):1158-62. Abstract
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Related News: Does G Protein Balancing Act Determine Antipsychotic Action?
Comment by: Bryan Roth
Submitted 8 February 2012
Posted 8 February 2012
Recent, quite provocative studies (Fribourg et al., 2011; Gonzalez-Maeso et al., 2008) have suggested that mGluR2 glutamate receptors and 5-HT2A serotonin receptors form a functional hetereodimeric complex, and that this complex mediates the actions of LSD-like hallucinogens and clozapine-like atypical antipsychotic drugs. The most recent paper also reported that the hetereodimeric complex facilitated 5-HT2A-serotonin signaling via Gi rather than its usual partner Gq. These are intriguing findings which, if generalizable, induce a paradigm shift in how we conceptualize the actions of these major drug classes. Additionally, these findings could fundamentally alter how we search for new antipsychotic drugs.
That being said, there are some controversial aspects of both papers which have been raised previously on this forum (see SRF related news story on Gonzalez-Maeso et al., 2008, with comments by Brian Dean and Gerard Marek).
Now a paper by Delille and colleagues has appeared online in Neuropharmacology that is likely to stoke the controversy (Delille et al., 2012). In this carefully controlled and executed study, a group of researchers from Abbott Pharmaceuticals report that they cannot replicate certain key findings of this paper, particularly related to the aforementioned unusual signal transduction pathways mediated by the hetereodimeric complex. Although they were able to replicate the biochemically based findings that mGluR2 and 5-HT2A can form a "complex," they report that this is relatively non-selective, as mGluR2 can interact with other GPCRs, including the 5-HT2B which is found most highly enriched in peripheral tissues.
Going forward, it will be important to see which of the sets of findings are more generally replicable: those of the Mt. Sinai lab or those from Abbott Pharmaceuticals.
Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD, Brezina V, Sealfon SC, Filizola M, González-Maeso J, Logothetis DE. Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell . 2011 Nov 23 ; 147(5):1011-23. Abstract
González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature . 2008 Mar 6 ; 452(7183):93-7. Abstract
Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M. Heterocomplex formation of 5-HT(2A)-mGlu(2) and its relevance for cellular signaling cascades. Neuropharmacology . 2012 Jan 25. Abstract
View all comments by Bryan Roth