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)

In this study we investigated the involvement of Ca2+ on the effects of alpha-ketoisocaproic acid (KIC), the main metabolite accumulating in maple syrup urine disease (MSUD), on the phosphorylating system associated with the intermediate filament (IF) proteins in slices from cerebral cortex of 9-day-old rats. We first observed that KIC significantly decreased the in vitro phosphorylation of IF proteins in brain slices. KIC-induced dephosphorylation was mediated especially by the protein phosphatase PP2B, a Ca2+-dependent protein phosphatase, but also by PP2A. We also demonstrated the involvement of Ca2+-dependent mechanisms in the KIC effects using the specific L-voltage-dependent Ca2+ channels (L-VDCC) inhibitor nifedipine, the NMDA antagonist DL-AP5 and the intracellular Ca2+ chelator BAPTA-AM. Blockage of Ca2+ channels or chelating intracellular Ca2+ completely prevented the effects of KIC on the phosphorylating system associated to IF proteins. In addition, we verified that KIC increased 45Ca2+ uptake in brain slices after 3 and 30 min incubation. Taken together, our present data indicate that KIC increase intracellular Ca2+ levels, probably promoting the activation of calcineurin. These results might be associated with the increased dephosphorylation of the IF proteins in slices of cerebral cortex of immature rats exposed to KIC at similar concentrations from those found in blood and tissues of patients with MSUD.
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PMID:Evidence that intracellular Ca2+ mediates the effect of alpha-ketoisocaproic acid on the phosphorylating system of cytoskeletal proteins from cerebral cortex of immature rats. 1611 8

Genetic defects in amino acid metabolism are major causes of newborn diseases that often lead to abnormal development and function of the central nervous system. Their direct impact on cardiac development and function has rarely been investigated. Recently, the authors have established that a mitochondrial targeted 2C-type ser/thr protein phosphatase, PP2Cm, is the endogenous phosphatase of the branched-chain alpha keto acid-dehydrogenase complex (BCKD) and functions as a key regulator in branched-chain amino acid catabolism and homeostasis. Genetic inactivation of PP2Cm in mice leads to significant elevation in plasma concentrations of branched-chain amino acids and branched-chain keto acids at levels similar to those associated with intermediate mild forms of maple syrup urine disease. In addition to neuronal tissues, PP2Cm is highly expressed in cardiac muscle, and its expression is diminished in a heart under pathologic stresses. Whereas phenotypic features of heart failure are seen in PP2Cm-deficient zebra fish embryos, cardiac function in PP2Cm-null mice is compromised at a young age and deteriorates faster by mechanical overload. These observations suggest that the catabolism of branched-chain amino acids also has physiologic significance in maintaining normal cardiac function. Defects in PP2Cm-mediated catabolism of branched-chain amino acids can be a potential novel mechanism not only for maple syrup urine disease but also for congenital heart diseases and heart failure.
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PMID:Catabolism of branched-chain amino acids in heart failure: insights from genetic models. 2121 99