In vitro findings of alterations in intracellular calcium homeostasis in schizophrenia

Bojarski, Łukasz; Debowska, Katarzyna; Wojda, Urszula

doi:10.1016/j.pnpbp.2010.08.020

Cited by 24 publications

(20 citation statements)

References 87 publications

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“…In fact, there is a growing body of convincing evidence pointing to a disturbance of calcium signaling in schizophrenia (Bojarski et al . ; Berridge ), and the results obtained in the present work suggest that especially CLO significantly influences calcium regulatory proteins.…”

Section: Discussionsupporting

confidence: 79%

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Clozapine influences cytoskeleton structure and calcium homeostasis in rat cerebral cortex and has a different proteomic profile than risperidone

Kędracka–Krok

Świderska

Jankowska

et al. 2015

Journal of Neurochemistry

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For over the last 50 years, the molecular mechanism of antipsychotic drugs' action has been far from clear. While risperidone is very often used in clinical practice, the most efficient known anti-psychotic drug is clozapine (CLO). However, the biochemical background of CLO's action still remains elusive. In this study, we performed comparative proteomic analysis of rat cerebral cortex following chronic administration of these two drugs. We observed significant changes in the expression of cytoskeletal, synaptic, and regulatory proteins caused by both antipsychotics. Among other proteins, alterations in collapsin response mediator proteins, CRMP2 and CRMP4, were the most spectacular consequences of treatment with both drugs. Moreover, risperidone increased the level of proteins involved in cell proliferation such as fatty acidbinding protein-7 and translin-associated factor X. CLO significantly up-regulated the expression of visinin-like protein 1, neurocalcin d and mitochondrial, stomatin-like protein 2, the calcium-binding proteins regulating calcium homeostasis, and the functioning of ion channels and receptors.

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Section: Discussionsupporting

confidence: 79%

“…), disturbed calcium homeostasis (Bojarski et al . ). Moreover, in patients suffering from schizophrenia, an extensive gray matter loss occurs in the cortex (Bennett ), which is thought to be related to dendritic spine pathology (Penzes et al .…”

mentioning

confidence: 97%

Clozapine influences cytoskeleton structure and calcium homeostasis in rat cerebral cortex and has a different proteomic profile than risperidone

Kędracka–Krok

Świderska

Jankowska

et al. 2015

Journal of Neurochemistry

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“…Simultaneously, dopamine receptor interacting proteins, including neuronal Ca 2+ sensors, are upregulated in schizophrenia [52]. Amongst other functions, dopamine regulates neuron excitability through both ligand-and voltage-gated ion channels [51,52]. As discussed above, CRMP2 overexpression increases Ca 2+ current density via CaV2.2 whereas lentiviral knockdown of CRMP2 reduces these densities with concomitant increase or decrease in vesicular neurotransmitter release [12].…”

Section: Crmp2 Associations With Neuropsychiatric Conditions Particumentioning

confidence: 97%

“…Primary disorders of schizophrenia, such as altered dopaminergic and glutamatergic neurotransmission, are being increasingly linked to dysregulated neuronal Ca 2+ homeostasis [51]. Simultaneously, dopamine receptor interacting proteins, including neuronal Ca 2+ sensors, are upregulated in schizophrenia [52]. Amongst other functions, dopamine regulates neuron excitability through both ligand-and voltage-gated ion channels [51,52].…”

Section: Crmp2 Associations With Neuropsychiatric Conditions Particumentioning

confidence: 99%

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

et al. 2011

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Collapsin response mediator protein-2 (DPYSL2 or CRMP2) is a multifunctional adaptor protein within the central nervous system. In the developing brain or cell cultures, CRMP2 performs structural and regulatory functions related to cytoskeletal dynamics, vesicle trafficking and synaptic physiology whereas CRMP2 functions in adult brain are still being elucidated. CRMP2 has been associated with several neuropathologic or psychiatric conditions including Alzheimer's disease (AD) and schizophrenia, either at the level of genetic polymorphisms; protein expression; post-translational modifications; or protein/protein interactions. In AD, CRMP2 is phosphorylated by glycogen synthase kinase-3β (GSK3β) and cyclin dependent protein kinase-5 (CDK5), the same kinases that act on tau protein in generating neurofibrillary tangles (NFTs). Phosphorylated CRMP2 collects in NFTs in association with the synaptic structure-regulating SRA1/WAVE1 (specifically Rac1-associated protein-1/WASP family verprolin-homologous protein-1) complex. This phenomenon could plausibly contribute to deficits in neural and synaptic structure that have been well documented in AD. This review discusses the essential biology of CRMP2 in the context of nascent data implicating CRMP2 perturbations as either a correlate of, or plausible contributor to, diverse neuropathologies. A discussion is made of recent findings that the atypical antidepressant tianeptine increases CRMP2 expression, whereas other, neuroactive small molecules including the epilepsy drug lacosamide and the natural brain metabolite lanthionine ketimine appear to bind CRMP2 directly with concomitant affects on neural structure. These findings constitute proofs-of-concept that pharmacological manipulation of CRMP2 is possible and hence, may offer new opportunities for therapy development against certain neurological diseases.

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“…One of the critical cellular function affected by ketamine is Ca 2+ -dependent signaling, which can mediate at least some of the psychotomimetic effects of ketamine (Lidow, 2003; Bojarski et al, 2010). It is because cytosolic Ca 2+ is a universal signaling messenger and disruption of the highly interdependent calcium-dependent enzymes leads to the propagation of aberrant signaling with long-lasting consequences on neuronal functioning.…”

Section: Introductionmentioning

confidence: 99%

Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction

Lisek

Ferenc

Studzian

et al. 2017

Front. Cell. Neurosci.

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Ketamine causes psychotic episodes and is often used as pharmacological model of psychotic-like behavior in animals. There is increasing evidence that molecular mechanism of its action is more complicated than just N-methyl-D-aspartic acid (NMDA) receptor antagonism and involves interaction with the components of calcium homeostatic machinery, in particular plasma membrane calcium pump (PMCA). Therefore, in this study we aimed to characterize brain region-specific effects of ketamine on PMCA activity, interaction with NMDA receptor through postsynaptic density protein 95 (PSD95) scaffolding proteins and glutamate release from nerve endings. In our study, ketamine induced behavioral changes in healthy male rats consistent with psychotic effects. In the same animals, we were able to demonstrate significant inhibition of plasma membrane calcium ATPase (PMCA) activity in cerebellum, hippocampus and striatum. The expression level and isoform composition of PMCAs were also affected in some of these brain compartments, with possible compensatory effects of PMCA1 substituting for decreased expression of PMCA3. Expression of the PDZ domain-containing scaffold protein PSD95 was induced and its association with PMCA4 was higher in most brain compartments upon ketamine treatment. Moreover, increased PSD95/NMDA receptor direct interaction was also reported, strongly suggesting the formation of multiprotein complexes potentially mediating the effect of ketamine on calcium signaling. We further support this molecular mechanism by showing brain region-specific changes in PSD95/PMCA4 spatial colocalization. We also show that ketamine significantly increases synaptic glutamate release in cortex and striatum (without affecting total tissue glutamate content), inducing the expression of vesicular glutamate transporters and decreasing the expression of membrane glutamate reuptake pump excitatory amino acid transporters 2 (EAAT2). Thus, ketamine-mediated PMCA inhibition, by decreasing total Ca2+ clearing potency, may locally raise cytosolic Ca2+ promoting excessive glutamate release. Regional alterations in glutamate secretion can be further driven by PSD95-mediated spatial recruitment of signaling complexes including glutamate receptors and calcium pumps, representing a novel mechanism of psychogenic action of ketamine.

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In vitro findings of alterations in intracellular calcium homeostasis in schizophrenia

Cited by 24 publications

References 87 publications

Clozapine influences cytoskeleton structure and calcium homeostasis in rat cerebral cortex and has a different proteomic profile than risperidone

Clozapine influences cytoskeleton structure and calcium homeostasis in rat cerebral cortex and has a different proteomic profile than risperidone

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

Glutamate Deregulation in Ketamine-Induced Psychosis—A Potential Role of PSD95, NMDA Receptor and PMCA Interaction

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