Abnormalities in the dopamine system in schizophrenia may lie in altered levels of dopamine receptor-interacting proteins

Bai, Jie; He, Fang; Novikova, Svetlana I.; Undie, Ashiwel S.; Dracheva, Stella; Haroutunian, Vahram; Lidow, Michael S.

doi:10.1016/j.biopsych.2004.06.022

Cited by 76 publications

(49 citation statements)

References 52 publications

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“…In addition, Frq might be involved in several human diseases, including schizophrenia, bipolar disorder and X-linked mental retardation (Koh et al, 2003;Bai et al, 2004;Bahi et al, 2003). Frq is highly conserved from yeast to humans, with 100% conservation amongst mammals (Burgoyne et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Frequenin/NCS-1 and the Ca2+-channel α1-subunit co-regulate synaptic transmission and nerve-terminal growth

Dason

Romero-Pozuelo

Marin

et al. 2009

Journal of Cell Science

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Drosophila Frequenin (Frq) and its mammalian and worm homologue, NCS-1, are Ca2+-binding proteins involved in neurotransmission. Using site-specific recombination in Drosophila, we created two deletions that removed the entire frq1 gene and part of the frq2 gene, resulting in no detectable Frq protein. Frq-null mutants were viable, but had defects in larval locomotion, deficient synaptic transmission, impaired Ca2+ entry and enhanced nerve-terminal growth. The impaired Ca2+ entry was sufficient to account for reduced neurotransmitter release. We hypothesized that Frq either modulates Ca2+ channels, or that it regulates the PI4Kβ pathway as described in other organisms. To determine whether Frq interacts with PI4Kβ with consequent effects on Ca2+ channels, we first characterized a PI4Kβ-null mutant and found that PI4Kβ was dispensable for synaptic transmission and nerve-terminal growth. Frq gain-of-function phenotypes remained present in a PI4Kβ-null background. We conclude that the effects of Frq are not due to an interaction with PI4Kβ. Using flies that were trans-heterozygous for a null frq allele and a null cacophony (encoding the α1-subunit of voltage-gated Ca2+ channels) allele, we show a synergistic effect between these proteins in neurotransmitter release. Gain-of-function Frq phenotypes were rescued by a hypomorphic cacophony mutation. Overall, Frq modulates Ca2+ entry through a functional interaction with the α1 voltage-gated Ca2+-channel subunit; this interaction regulates neurotransmission and nerve-terminal growth.

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Section: Introductionmentioning

confidence: 99%

Frequenin/NCS-1 and the Ca2+-channel α1-subunit co-regulate synaptic transmission and nerve-terminal growth

Dason

Romero-Pozuelo

Marin

et al. 2009

Journal of Cell Science

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“…Calcyon is a single transmembrane protein expressed in brain [1;2] that has been linked to neuropsychiatric disorders such as schizophrenia in which expression of this protein is upregulated in the prefrontal cortex (PFC) and thalamus [3][4][5][6]. Recent molecular studies indicate that calcyon primarily interacts with clathrin light chain and enhances clathrin-mediated endocytosis (CME) [7].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice

Trantham-Davidson¹,

Vazdarjanova²,

Dai³

et al. 2008

Behavioural Brain Research

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Gene linkage and association studies have implicated the region of chromosome 10q containing the calcyon locus with attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia susceptibility. In addition, levels of calcyon protein and transcripts are also significantly increased in postmortem tissue from schizophrenic brains. But whether altered calcyon expression might be part of the disease etiology or merely a patho-physiological side effect is not known. To begin to address this issue, we generated a transgenic mouse line (Cal OE ) using the human calcyon cDNA in which calcyon expression is up-regulated in a number of forebrain structures including the hippocampus, prefrontal cortex, striatum, and amygdala. Compared to control littermates, the Cal OE mice display a range of abnormal behaviors including spontaneous hyperactivity, reduced anxiety, and/or impaired restraint (harm avoidance) that would indicate that calcyon up-regulation leads to deficits in control over behavioral output.

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“…It has now become clear that dopamine receptors, as well as most GPCRs, exist as components of preformed signaling complexes that can consist of G proteins, enzymes, scaffolding proteins, and other receptors (8 -10). Indeed, a number of dopamine receptor-interacting proteins have now been identified, some of which may affect receptor trafficking and expression or may be altered in neuropsychiatric disorders (11,12).…”

mentioning

confidence: 99%

D1 and D2 Dopamine Receptor Expression Is Regulated by Direct Interaction with the Chaperone Protein Calnexin

Free¹,

Hazelwood²,

Cabrera

et al. 2007

Journal of Biological Chemistry

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As for all proteins, G protein-coupled receptors (GPCRs) undergo synthesis and maturation within the endoplasmic reticulum (ER). The mechanisms involved in the biogenesis and trafficking of GPCRs from the ER to the cell surface are poorly understood, but they may involve interactions with other proteins. We have now identified the ER chaperone protein calnexin as an interacting protein for both D 1 and D 2 dopamine receptors. These proteinprotein interactions were confirmed using Western blot analysis and co-immunoprecipitation experiments. To determine the influence of calnexin on receptor expression, we conducted assays in HEK293T cells using a variety of calnexin-modifying conditions. Inhibition of glycosylation either through receptor mutations or treatments with glycosylation inhibitors partially blocks the interactions with calnexin with a resulting decrease in cell surface receptor expression. Confocal fluorescence microscopy reveals the accumulation of D 1 -green fluorescent protein and D 2 -yellow fluorescent protein receptors within internal stores following treatment with calnexin inhibitors. Overexpression of calnexin also results in a marked decrease in both D 1 and D 2 receptor expression. This is likely because of an increase in ER retention because confocal microscopy revealed intracellular clustering of dopamine receptors that were co-localized with an ER marker protein. Additionally, we show that calnexin interacts with the receptors via two distinct mechanisms, glycan-dependent and glycan-independent, which may underlie the multiple effects (ER retention and surface trafficking) of calnexin on receptor expression. Our data suggest that optimal receptor-calnexin interactions critically regulate D 1 and D 2 receptor trafficking and expression at the cell surface, a mechanism likely to be of importance for many GPCRs.

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Abnormalities in the dopamine system in schizophrenia may lie in altered levels of dopamine receptor-interacting proteins

Cited by 76 publications

References 52 publications

Frequenin/NCS-1 and the Ca2+-channel α1-subunit co-regulate synaptic transmission and nerve-terminal growth

Frequenin/NCS-1 and the Ca2+-channel α1-subunit co-regulate synaptic transmission and nerve-terminal growth

Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice

D1 and D2 Dopamine Receptor Expression Is Regulated by Direct Interaction with the Chaperone Protein Calnexin

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