G protein-coupled receptors in major psychiatric disorders

Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, HHS, Bethesda, MD 20892, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 05/2007; 1768(4):976-93. DOI: 10.1016/j.bbamem.2006.09.025
Source: PubMed

ABSTRACT Although the molecular mechanisms underlying psychiatric illnesses such as depression, bipolar disorder and schizophrenia remain incompletely understood, there is increasing clinical, pharmacologic, and genetic evidence that G protein-coupled receptors (GPCRs) play critical roles in these disorders and their treatments. This perspectives paper reviews and synthesizes the available data. Dysfunction of multiple neurotransmitter and neuropeptide GPCRs in frontal cortex and limbic-related regions, such as the hippocampus, hypothalamus and brainstem, likely underlies the complex clinical picture that includes cognitive, perceptual, affective and motoric symptoms. The future development of novel agents targeting GPCR signaling cascades remains an exciting prospect for patients refractory to existing therapeutics.

Download full-text


Available from: Alberico L Catapano, Jul 02, 2015
  • Source
    [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 · 4.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Psychiatric disorders are often considered as simple imbalances between a limited number of cerebral neurotransmitters. In fact, it is more complicated than this “simple approach” and each psychiatric disorder constitutes network dysfunction within which several agents and factors are implicated. Thus, the therapeutical perspectives and implications are as vast and as numerous as the diversity of those network dysfunctions. Furthermore, the description of factors influencing diseases prognoses and treatment efficacy indicates new elements to consider both in therapies and drug researches.
    Saudi Pharmaceutical Journal 04/2014; 22(2):95–100. DOI:10.1016/j.jsps.2013.01.008 · 1.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peptide mimics of intracellular loop 2 (ic2) of the human 5HT1a receptor have been studied with respect to their ability to inhibit agonist binding via interference with receptor-G-protein coupling. These peptides give shallow concentration-effect relationships. Additionally, these peptides have been studied with respect to their ability to trigger the signal transduction system of this Gi-coupled receptor. Two signaling parameters have been quantified: concentration of intracellular cAMP and changes in incorporation into the G protein of a stable analog of GTP. In both cases, peptide mimics near midloop of ic2 actually show agonist activity with efficacy falling off toward both loop termini near TM 3 and TM 4. Previous results have suggested that the loop region near the TM3/ic2 interface is primarily responsible for receptor-G-protein coupling, while the current result emphasizes the mid-ic2 loop region's ability to activate the G protein following initial coupling. A limited number of peptides from the receptor's TM5/ic3 loop vicinity were also studied regarding agonist inhibition and G-protein activation. These peptides provide additional evidence that the human 5HT1a receptor, TM5/ic3 loop region, is involved in both coupling and activation actions. Overall, these results provide further information about potential pharmacological intervention and drug development with respect to the human 5HT1a receptor/G-protein system. Finally, the structural evidence generated here provides testable models pending crystallization and X-ray analysis of the receptor.
    International Journal of Peptides 05/2012; 2012:490734. DOI:10.1155/2012/490734