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)

Fluoxetine (Prozac) is the most widely prescribed medication for the treatment of depression. Nevertheless, little is known about the molecular basis of its clinical efficacy, apart from the fact that fluoxetine increases the synaptic availability of serotonin. Here we show that, in vivo, fluoxetine, given either acutely or chronically, regulates the phosphorylation state of dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) at multiple sites in prefrontal cortex, hippocampus, and striatum. Acute administration of fluoxetine increases phosphorylation of DARPP-32 at the protein kinase A site, Thr-34, and at the casein kinase-1 site, Ser-137, and decreases phosphorylation at the cyclin-dependent kinase 5 site, Thr-75. Each of these changes contributes, through distinct signaling pathways, to increased inhibition of protein phosphatase-1, a major serine/threonine protein phosphatase in the brain. Fluoxetine also increases phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 at Ser-831 and Ser-845. Both the fluoxetine-mediated increase in AMPA receptor phosphorylation at Ser-845-GluR1 and the beneficial responsiveness to fluoxetine in an animal test of antidepressant efficacy were strongly reduced in DARPP-32 knockout mice, indicating a critical role for this phosphoprotein in the antidepressant actions of fluoxetine. Mice chronically treated with fluoxetine had increased levels of DARPP-32 mRNA and protein and a decreased ability to increase phospho-Ser-137-DARPP-32 and phospho-Ser-831-GluR1. These chronic changes may be relevant to the delayed onset of therapeutic efficacy of fluoxetine.
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PMID:Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). 1188 Jun 51

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%.
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PMID:Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience. 1655 35