Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest of biological psychiatry. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients. We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from the Stanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopamine receptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol consumption, or antipsychotic and mood stabilizing medications. The present study supports the hypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopamine receptor-interacting proteins.
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PMID:Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients. 1249 48

Abnormal activity of the dopamine system has been implicated in several psychiatric and neurological illnesses; however, lack of knowledge about the precise sites of dopamine dysfunction has compromised our ability to improve the efficacy and safety of dopamine-related drugs used in treatment modalities. Recent work suggests that dopamine transmission is regulated via the concerted efforts of a cohort of cytoskeletal, adaptor and signaling proteins called dopamine receptor-interacting proteins (DRIPs). The discovery that two DRIPs, calcyon and neuronal Ca(2+) sensor 1 (NCS-1), are upregulated in schizophrenia highlights the possibility that altered protein interactions and defects in Ca(2+) homeostasis might contribute to abnormalities in the brain dopamine system in neuropsychiatric diseases.
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PMID:Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. 1296 74

Structures of the cerebral cortex expressing the D2 dopamine receptor subtype (D2) are important sites of action of antipsychotic drugs. It has also been repeatedly suggested that the prefrontal cortex plays a significant role in neuropsychiatric disorders, including schizophrenia. Here, by using single and double immunohistochemical techniques with electron microscopy, we investigated in the primate prefrontal cortex the ultrastructural localization of D2 and we compared it with that of the neuronal calcium sensor-1 (NCS-1), a neuron-specific calcium-binding and D2-interacting protein. D2 immunoreactivity, revealed with preembedding immunoperoxidase in single labeling and with preembedding immunogold for double labeling, was localized in cell bodies with ultrastructural characteristics of both neurons and astroglia. D2 was localized in pre- and postsynaptic structures, including spines and dendrites, and in both excitatory- and inhibitory-like axon terminals. Immunogold labeling revealed peri- and extrasynaptic localization of D2 in postsynaptic structures, whereas extrasynaptic labeling was typically found in boutons. NSC-1 immunoreactivity was abundant in pre- and postsynaptic structures, in which it was also colocalized with D2. With the present strategy (that has high resolution but relatively limited sensitivity), NSC-1 was observed in about 10% of the D2-immunopositive spines and in a lower proportion of D2-immunopositive dendrites and boutons. The data demonstrate the localization of D2 in pre- and postsynaptic as well as extra- and perisynaptic structures of the primate prefrontal cortex. The data also show the coexistence of NCS-1 and D2 at the ultrastructural level. The latter finding suggests a role for NCS-1 in desensitization of D2 in the prefrontal cortex.
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PMID:Subcellular localization of the dopamine D2 receptor and coexistence with the calcium-binding protein neuronal calcium sensor-1 in the primate prefrontal cortex. 1597 84

Caldendrin is a neuronal calcium sensor protein that is tightly associated with the postsynaptic density (PSD) of excitatory synapses. It has an established role in synapto-dendritic Ca(2+)-signaling as a multifunctional regulator of intracellular Ca(2+) levels. Previous work has shown that expression levels of protein components involved in signaling processes at excitatory synapses are significantly altered in the brains of schizophrenic patients. Furthermore, it is widely accepted that synaptic pathology associated with the glutamatergic N-methyl-d-aspartate (NMDA) receptor is a feature of the disease. Here we report that in postmortem brains of chronic schizophrenics (N: 12) as compared to age-and sex-matched controls (N: 12) the number of Caldendrin-immunoreactive neurons are significantly reduced in the left dorsolateral prefrontal cortex, a brain region prominently associated with schizophrenia. Less dramatic changes were observed in other cortical regions. However, despite the reduced number of immunoreactive neurons, absolute Caldendrin protein levels were elevated and no change in Caldendrin PSD-levels were observed as compared to the left dorsolateral prefrontal cortex in the normal human brain. Thus, synapto-dendritic Ca(2+)-signaling via Caldendrin is altered in schizophrenic patients by a redistribution of the protein into a lower number of pyramidal neurons, which express higher Caldendrin levels. Since Caldendrin is a multivalent regulator of voltage dependent Ca(2+)-channels and Ca(2+)-release channels the loss of Caldendrin mediated synapto-dendritic Ca(2+)-signaling processes in some neurons together with its concurrent upregulation in others should profoundly change their synapto-dendritic Ca(2+)-signaling. These observations add to existing evidence for a de-regulation of neuronal Ca(2+)-signaling in schizophrenia.
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PMID:A reduced number of cortical neurons show increased Caldendrin protein levels in chronic schizophrenia. 1771 5

Dopamine-mediated neurotransmission imbalances are associated with several psychiatry illnesses, such as schizophrenia. Recently it was demonstrated that two proteins involved in dopamine signaling are altered in prefrontal cortex (PFC) of schizophrenic patients. DARPP-32 is a key downstream effector of intracellular signaling pathway and is downregulated in PFC of schizophrenic subjects. NCS-1 is a neuronal calcium sensor that can inhibit dopamine receptor D2 internalization and is upregulated in PFC of schizophrenic subjects. It is well known that dopamine D2 receptor is the main target of antipsychotic. Therefore, our purpose was to study if chronic treatment with typical or atypical antipsychotics induced alterations in DARPP-32 and NCS-1 expression in five brain regions: prefrontal cortex, hippocampus, striatum, cortex and cerebellum. We did not find any changes in DARPP-32 and NCS-1 protein expression in any brain region investigated.
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PMID:DARPP-32 and NCS-1 expression is not altered in brains of rats treated with typical or atypical antipsychotics. 1776 44

Visinin-like protein-1 (VILIP-1) belongs to the neuronal calcium sensor (NCS) family of EF-hand Ca(2+)-binding proteins which are involved in a variety of Ca(2+)-dependent signal transduction processes in neurons. VILIP-1 has been implicated in the pathology of CNS disorders including Alzheimer's disease and schizophrenia, but its expression has also been found to be regulated following induction of hippocampal synaptic plasticity underlying learning and memory processes. VILIP-1 is strongly expressed in different populations of principal and non-principal neurons in the rat hippocampus. VILIP-1-containing interneurons are morphologically and neurochemically heterogeneous. On the basis of co-localizing markers, VILIP-1 is rarely present in perisomatic inhibitory parvalbumin containing cells. However, VILIP-1 is frequently expressed in mid-proximal dendritic inhibitory cells characterized by calbindin immunoreactivity, and most strongly co-expressed in calretinin-positive disinhibitory interneurons. Partial co-localization of the metabotropic glutamate receptor mGluR1alpha with VILIP-1 was often found in interneurons located in the stratum oriens of the hippocampal CA1 region and in hilar interneurons. Partial co-localization of alpha4beta2 nicotinic acetylcholine receptor with VILIP-1 was seen in stratum oriens interneurons and particularly at the border of the hilus in the dentate gyrus, where VILIP-1 also strongly co-localized with calretinin. We speculate that depending on the regulation of the expression of VILIP-1 in hippocampal pyramidal cells or defined types of interneurons, it may have different effects on hippocampal synaptic plasticity and network activity in health and disease.
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PMID:Expression of the neuronal calcium sensor visinin-like protein-1 in the rat hippocampus. 1844 Jul 8

D2 dopamine receptors (D2Rs) represent an important class of receptors in the pharmacological development of novel therapeutic drugs for the treatment of schizophrenia. Recent research into D2R signaling suggests that receptor properties are dependent on interaction with a cohort of dopamine receptor interacting proteins (DRIPs) within a macromolecular structure termed the signalplex. One component of this signalplex is neuronal calcium sensor 1 (NCS-1) a protein found to regulate the phosphorylation, trafficking, and signaling profile of the D2R in neurons. It has also been found that NCS-1 can contribute to the pathology of schizophrenia and may play a role in the efficacy of antipsychotic drug medication in the brain. In this review we discuss how the selective targeting of a DRIP, such as NCS-1, can be utilized as a novel strategy of drug design for the creation of new therapeutics for a disease such as schizophrenia. Using a fluorescence polarization assay we explore how the ability to detect changes in D2R/NCS-1 interaction can be exploited as an effective screening tool in the isolation and development of lead compounds for antipsychotic drug development. This line of work explores a novel direction in targeting D2Rs via their signalplex components and supports the notion that receptor interacting proteins represent an emerging new class of molecular targets for pharmacological drug development.
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PMID:Dopamine receptor interacting proteins: targeting neuronal calcium sensor-1/D2 dopamine receptor interaction for antipsychotic drug development. 2177 87

The calcium-binding protein frequenin (Frq), discovered in the fruit fly Drosophila, and its mammalian homologue neuronal calcium sensor 1 (NCS-1) have been reported to affect several aspects of synaptic transmission, including basal levels of neurotransmission and short- and long-term synaptic plasticities. However, discrepant reports leave doubts about the functional roles of these conserved proteins. In this review, we attempt to resolve some of these seemingly contradictory reports. We discuss how stimulation protocols, sources of calcium (voltage-gated channels versus internal stores), and expression patterns (presynaptic versus postsynaptic) of Frq may result in the activation of various protein targets, leading to different synaptic effects. In addition, the potential interactions of Frq's C-terminal and N-terminal domains with other proteins are discussed. Frq also has a role in regulating neurite outgrowth, axonal regeneration, and synaptic development. We examine whether the effects of Frq on neurotransmitter release and neurite outgrowth are distinct or interrelated through homeostatic mechanisms. Learning and memory are affected by manipulations of Frq probably through changes in synaptic transmission and neurite outgrowth, raising the possibility that Frq may be implicated in human pathological conditions, including schizophrenia, bipolar disorder, and X-linked mental retardation.
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PMID:Multiple roles for frequenin/NCS-1 in synaptic function and development. 2239 13

Sensing and regulating intracellular levels of calcium are essential for proper cellular function. In neurons, calcium sensing plays important roles in neuronal plasticity, neurotransmitter release, long-term synapse modification and ion channel activity. Neuronal calcium sensor-1 (NCS-1) is a member of the highly conserved neuronal calcium sensor family. Although NCS-1 has been associated with psychiatric conditions including autism, bipolar disorder and schizophrenia, it is unclear which role NCS-1 plays in behavior. To understand the involvement of NCS-1 in psychiatric conditions, we provided a comprehensive behavioral characterization of NCS-1 knockout (KO) mice. These mice grow and develop normally without apparent abnormalities in comparison to wild type littermates. However, open field showed that NCS-1 deficiency impairs novelty-induced exploratory activity in both KO and heterozygote (HT) mice. Moreover, NCS-1-deficiency also resulted in anxiety- and depressive-like behaviors as demonstrated by elevated plus maze, large open field, forced swim and tail suspension tasks. Furthermore, based on spontaneous object recognition test, non-aversive long-term memory was impaired in NCS-1 KO mice. In contrast, neither social behavior nor a kind of aversive memory was affected under NCS-1 deficiency. These data implicate NCS-1 in exploratory activity, memory and mood-related behaviors, suggesting that NCS-1 gene ablation may result in phenotypic abnormalities associated with neuropsychiatric disorders.
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PMID:NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non-aversive memory in mice. 2463 52

The pedunculopontine nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular nucleus (Pf), and pontine subcoeruleus nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS.
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PMID:Pedunculopontine Nucleus Gamma Band Activity-Preconscious Awareness, Waking, and REM Sleep. 2536 99


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