Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients

Koh, Phil-Ok; Undie, Ashiwel S.; Kabbani, Nadine; Levenson, Robert; Goldman‐Rakic, Patricia S.; Lidow, Michael S.

doi:10.1073/pnas.232693499

Cited by 188 publications

(150 citation statements)

References 61 publications

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“…It is suggested that alterations in the DA system in the brain of schizophrenics occurs during development and may not be due to secondary effects of drug treatment (Albert et al, 2002;Koh et al, 2003;Souza et al, 2008Souza et al, , 2010. The main target for antipsychotics, the DA receptor D 2 , modulates the Akt pathway in mammals (Lai et al, 2006;Beaulieu et al, 2007;Tan et al, 2008), and our data show that this effect is conserved in zebrafish.…”

Section: Discussionsupporting

confidence: 51%

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Souza¹,

Romano-Silva²,

Tropepe³

2011

J. Neurosci.

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An imbalance in dopamine-mediated neurotransmission is a hallmark physiological feature of neuropsychiatric disorders, such as schizophrenia. Recent evidence demonstrates that dopamine D 2 receptors, which are the main target of antipsychotics, modulate the activity of the protein kinase Akt, which is known to be downregulated in the brain of patients with schizophrenia. Akt has an important role in the regulation of cellular processes that are critical for neurodevelopment, including gene transcription, cell proliferation, and neuronal migration. Thus, it is possible that during brain development, altered Akt-dependent dopamine signaling itself may lead to defects in neural circuit formation. Here, we used a zebrafish model to assess the direct impact of altered dopamine signaling on brain development and larval motor behavior. We demonstrate that D 2 receptor activation acutely suppresses Akt activity by decreasing the level of pAkt(Thr308) in the larval zebrafish brain. This D 2 -dependent reduction in Akt activity negatively regulates larval movement and is distinct from a D 1 -dependent pathway with opposing affects on motor behavior. In addition, we show that D 2 -dependent suppression of Akt activity causes a late onset change in GSK3b activity, a known downstream target of Akt signaling. Finally, altered D 2 receptor signaling, or direct inhibition of Akt activity, causes a significant decrease in the size of the GABAergic neuron population throughout most of the brain. Our observations suggest that D 2 receptor signaling suppresses Akt-GSK3b activity, which regulates GABAergic neuron development and motor behavior.

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Section: Discussionsupporting

confidence: 51%

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Souza¹,

Romano-Silva²,

Tropepe³

2011

J. Neurosci.

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“…With regard to the Ins(1,4,5) P 3 /Ca 2+ pathway, there are a number of observations indicating that the resting and activated levels of Ca 2+ are elevated in BD. 30 The neuronal Ca 2+ sensor-1 (NCS-1), which is known to be elevated in the prefrontal cortex in both BD and schizophrenia, 34 is known to enhance the activity of the Ins(1,4,5)P 3 Rs 35 and this would contribute to an increase in the intracellular level of Ca 2+ . Increase NCS-1 activity may also influence membrane excitability by desensitizing the D2 receptors.…”

Section: Bipolar Disordermentioning

confidence: 99%

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Berridge

2013

Prion

184

129

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“…NCS-1 has also been linked to serious neurodegenerative disorders including schizophrenia, bipolar disorder (BD) (32), and autism (33,34). However, the dysfunctions of NCS-1 are poorly characterized on the molecular level, and whether they involve altered functional profiles or loss of function due to formation of misfolded states is currently unknown.…”

Section: Significancementioning

confidence: 99%

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

Heidarsson

Naqvi

Otazo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurodegenerative disorders are strongly linked to protein misfolding, and crucial to their explication is a detailed understanding of the underlying structural rearrangements and pathways that govern the formation of misfolded states. Here we use singlemolecule optical tweezers to monitor misfolding reactions of the human neuronal calcium sensor-1, a multispecific EF-hand protein involved in neurotransmitter release and linked to severe neurological diseases. We directly observed two misfolding trajectories leading to distinct kinetically trapped misfolded conformations. Both trajectories originate from an on-pathway intermediate state and compete with native folding in a calcium-dependent manner. The relative probability of the different trajectories could be affected by modulating the relaxation rate of applied force, demonstrating an unprecedented real-time control over the free-energy landscape of a protein. Constant-force experiments in combination with hidden Markov analysis revealed the free-energy landscape of the misfolding transitions under both physiological and pathological calcium concentrations. Remarkably for a calcium sensor, we found that higher calcium concentrations increased the lifetimes of the misfolded conformations, slowing productive folding to the native state. We propose a rugged, multidimensional energy landscape for neuronal calcium sensor-1 and speculate on a direct link between protein misfolding and calcium dysregulation that could play a role in neurodegeneration.protein folding | NCS-1 | off-pathway intermediate | conformational dynamics | optical trapping

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Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients

Cited by 188 publications

References 61 publications

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

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Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients

Cited by 188 publications

References 61 publications

Dopamine D2Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine D2Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1

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Product

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Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae

Dopamine D₂Receptor Activity Modulates Akt Signaling and Alters GABAergic Neuron Development and Motor Behavior in Zebrafish Larvae