Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) mediate antidepressant-sensitive clearance of 5-HT following release. Although we have been aware for decades that SERT-mediated 5-HT clearance can be modulated by exogenous agents including serotonin-selective reuptake inhibitors, amphetamines, and cocaine, we have had little reason to speculate that SERT activity was actively controlled through endogenous pathways. Recent studies indicate that SERTs are likely to be trafficked to specific plasma membrane subdomains to achieve localized clearance of 5-HT, and that the number of SERTs resident in the plasma membrane is controlled through kinase- and phosphatase-linked pathways. In particular, roles for protein kinase C and phosphatase 2A become apparent through studies with enzyme activators and inhibitors in SERT-transfected cells, where SERT proteins are rapidly phosphorylated in parallel with transporter redistribution and loss of functional uptake capacity. Based on our findings, and the studies of others in native tissues and transfected cells, we propose a model whereby SERTs are organized in a macromolecular complex in the plasma membrane that may serve to locate reuptake activity near release sites. Although many elements of this model remain hypothetical, our findings suggest a much more dynamic picture of transporter-mediated 5-HT reuptake than typically described and suggest opportunities both for the development of new SERT regulatory agents and for the identification of regulatory pathways that may be compromised in mental illness.
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PMID:Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. 969 89

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurin-related genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin gamma catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis.
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PMID:Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. 1285 58

It remains elusive what factors affect posterior reversible encephalopathy syndrome (PRES). Eleven PRES children, all with acute glomerulonephritis, Alport syndrome, and lupus nephritis, 5 with nephrosis, and 3 renal transplant recipients, were studied. PRES recurred in 1 patient. Neurological symptoms were graded as 1: mild (headache, nausea/vomiting, or tremor), 2: moderate (vision change), and 3: severe (mental dysfunction, cerebellar symptoms, seizures, recurrence of seizures, and coma). Magnetic resonance imaging was graded as 1: subtle change, 2: abnormal large areas, and 3: complete involvement of the regions. The common symptoms were seizures (100%), headache (82%), nausea/vomiting (73%), coma (55%), and vision change (46%). Seizures recurred in 7 (64%). All but one (91%) developed hypertension and 7 (64%) received calcineurin inhibitors (CNI). Edema occurred in 7 (64%) and renal insufficiency/end-stage renal disease (ESRD) in 4 (36%). Seizures recurred frequently in younger patients. Symptoms were severe in girls. Duration or severity of the condition with predisposing factors (hypertension, CNI, nephrosis or renal insufficiency/ERSD) did not make a difference in the symptoms and neuroimaging. Two patients developed chronic epilepsy. Age and gender may affect PRES symptoms. Our results are limited by small sample size and should be determined using larger numbers of patients.
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PMID:Age and gender may affect posterior reversible encephalopathy syndrome in renal disease. 2182 8

Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.
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PMID:Mental health disorders and solid-organ transplant recipients. 2374 26

Psychotic disorders are a group of psychiatric disorders characterized by the presence of delusions, hallucinations, bizarre behavior, and disorganized speech. There are several possible causes for the occurrence of psychotic disorders in patients who underwent solid organ transplant, including pre-existing mental illness, electrolyte disturbances, infections of the central nervous system, and adverse reaction to drugs. Calcineurin inhibitors are a class of immunosuppressive drugs, such as tacrolimus and cyclosporine, that are currently considered the mainstay in the immunosuppressive drug regimen of patients who underwent solid organ transplant. Neurotoxicity is one of the adverse reactions associated with the use of calcineurin inhibitors, ranging from upper limb tremors to psychotic disorders and seizures. We report the cases of 2 liver transplant recipients who developed severe psychotic disorder 1 month after the procedure. After an extensive investigation for other possible triggers of psychiatric disease, the use of tacrolimus was considered to be the most likely cause for the acute psychotic disorder. In less than 24 hours after suspension of that drug, all symptoms disappeared in both patients, making a causal relationship with tacrolimus even more likely. The patients were then given cyclosporine, another drug from the same class, allowing for adequate immunosuppression and preserved graft function, with no further psychiatric symptoms. This report confirms that a 24-hour trial of tacrolimus suspension can be safe and effective in the diagnosis of drug-related psychotic disorders in patients who underwent liver transplant. This article is compliant with the Helsinki Congress and the Istanbul Declaration.
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PMID:Tacrolimus-Associated Psychotic Disorder: A Report of 2 Cases. 3219 65

Rapamycin inhibits protein translation in cells, including neural stem cells (NSCs), by suppressing the mechanistic target of rapamycin (mTOR). This drug has been widely used together with calcineurin inhibitors in transplantation patients to prevent graft rejection. Previous studies have reported an association between mTOR and depression, but few investigations of this have occurred in transplant recipients. We have here tested the psychiatric effects of rapamycin in mice. The animals treated with rapamycin showed decreased locomotion and sugar consumption. In these rapamycin-treated mice also, the granule cells in the dentate gyrus (DG), which actively differentiate and proliferate from NSC, showed decreases in both excitatory and inhibitory synaptic transmission. Furthermore, the SOX2/NeuN ratio in the DG was decreased in mice treated with rapamycin. We further show that kidney transplantation patients who are receiving rapamycin have more psychiatric disorder such as adjustment disorder. Clinical attention is thus needed when administering rapamycin to transplant recipients due to its behavioral effects and its impact on NSC.
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PMID:Rapamycin increases the incidence of neuropsychiatric illness in kidney transplant patients through the suppression of neural stem cells. 3242 20