Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs

Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cell (Impact Factor: 32.24). 11/2011; 147(5):1011-23. DOI: 10.1016/j.cell.2011.09.055
Source: PubMed

ABSTRACT Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

Download full-text


Available from: Terrell Holloway, Sep 28, 2015
46 Reads
  • Source
    • "However, a recent study provides both in vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the mGlu2/3 receptor agonists LY354740 and LY379268 (Fell et al., 2009). Interestingly, a direct 5-HT2AR– mGluR2 interaction between the receptor complex seems to be involved in the altered cortical processes of SZ, providing a promising target for the treatment of psychosis (Fribourg et al., 2011; Gonzalez- Maeso et al., 2008). Further, glutamate and GABA are the major excitatory and inhibitory neurotransmitters that are critical for normal neuronal signaling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists' mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2015; 60. DOI:10.1016/j.pnpbp.2015.02.012 · 3.69 Impact Factor
  • Source
    • "Dopamine D2 receptor blockade is a shared feature of these widely used drugs, but it does not appear to be their sole mechanism of action (Grunder et al., 2009; Meltzer, 2013). Other targets likely to be relevant for the therapeutic effects of antipsychotics include cholinergic receptors (Ibrahim and Tamminga, 2011), glutamate and serotonin receptors (Fribourg et al., 2011; Fell et al., 2012; de Bartolomeis et al., 2013), and α-1 noradrenergic receptors (Cohen and Lipinski, 1986; Ma et al., 2006). These examples are not meant to be exhaustive, but are listed here to illustrate the point that antipsychotics are multi-target drugs (Roth et al., 2004) with additional molecular mechanisms yet to be elucidated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.
    Frontiers in Pharmacology 07/2014; 5:177. DOI:10.3389/fphar.2014.00177 · 3.80 Impact Factor
  • Source
    • "PDZ domain–containing proteins of the PSD-95/ SAP97 family have an established link to the regulation and treatment of mood disorders and psychiatric disease that may implicate 5HT 2A R signaling (Gray and Roth, 2001; Roth and Xia, 2004; Catapano and Manji, 2007). The efficacy of second-generation atypical antipsychotics appears to be dependent on their ability to downregulate 5HT 2A R-mediated signaling , while upregulating metabotropic–glutamate receptor 2 (mGluR2) signaling (Fribourg et al., 2011). In the current study, we achieved downregulation of 5HT 2A R signaling by preventing the interaction of SAP97 with 5HT 2A R, thereby providing a novel strategy for manipulating 5HT 2A R function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Serotonin (5-HT) interacts with a wide variety of 5-HT receptors (5-HTR) of which 5-HT2AR plays an important target for antidepressant and atypical antipsychotic drugs. The carboxyl-terminal tail of 5-HT2AR encodes a motif that mediates interactions with PSD-95/Discs Large/Zona Occludens 1 (PDZ) domain containing proteins. In the present study, we found that 5-HT2AR interacts with synapse-associated protein 97 (SAP97; also known as DLG1) by co-immunoprecipitation in human embryonic 293 (HEK 293) cells and cortical brain lysates. We find that 5-HT2AR expression results in the recruitment of SAP97 from the cytosol to the plasma membrane and that this recruitment is dependent upon an intact 5-HT2AR PDZ binding motif. We also show that 5-HT2AR interacts with SAP97 using bioluminescence energy transfer and that overexpression of SAP97 retards 5-HT2AR endocytosis, while single hair pin RNA knockdown facilitates 5-HT2AR internalization. The knockdown of SAP97 in HEK 293 cells results in a reduction in the maximum efficacy for 5-HT2AR-stimulated inositol phosphate formation and that the deletion of the 5-HT2AR PDZ motif also impairs 5-HT2AR signaling. Similar to what has been observed for the corticotropin releasing factor receptor 1 (CRFR1), SAP97 expression is essential for 5-HT2AR-stimulated ERK1/2 phosphorylation by a PDZ interaction-independent mechanism. Moreover, we find that SAP97 is not responsible for CRFR1-mediated sensitization of 5-HT2AR signaling. Taken together, our studies show that SAP97 plays a conserved role in regulating 5-HT2AR endocytosis and ERK1/2 signaling, but plays a novel role in regulating 5-HT2AR G protein coupling.
    Molecular pharmacology 07/2014; 86(3). DOI:10.1124/mol.114.093476 · 4.13 Impact Factor
Show more