Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.1 (Mg2+-ATPase)
 1,484 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Altered membrane integrity has been suggested as a major factor in the development of cellular injury during myocardial necrosis. The present study was designed to investigate the effect of diosgenin on lysosomal hydrolases, membrane-bound enzymes, and electrolytes during isoproterenol (ISO)-induced myocardial necrosis in rats. Animals were pretreated with DIOS (80 mg/kg) for a period of 35 days. Myocardial infarction was experimentally induced with ISO (85 mg/kg) twice at 24 h interval. Experimental myocardial infarction was evidenced with marked elevation of creatine kinase-MB (CK-MB) in serum with concomitant increase in lipid peroxidation (plasma thiobarbituric acid reactive substances (TBARS) and hydroperoxides (HP)). Activity of lysosomal hydrolases (beta-glucuronidase, beta-N-acetyl glucosaminidase, beta-D-galactosidase, cathepsin D, and acid phosphatase) was found to be increased in serum and heart tissue of ISO-alone treated animals. DIOS (80 mg/kg) pretreated groups showed significant decrease in CK-MB, lipid peroxidation, and lysosomal hydrolases activity. The membrane-bound enzymes such as Ca2+-ATPase and Mg2+-ATPase activity was increased and Na+/K+-ATPase activity was decreased in the heart tissues of ISO-alone treated animals. These enzyme alterations lead to the change in the electrolytes content such as sodium, potassium, and calcium in the heart tissue. However, DIOS (80 mg/kg) pretreatment reversed the membrane-bound enzymes activity and thereby maintained the normal electrolyte concentration. These results suggest the protective action of diosgenin in ISO-induced myocardial infarction. The salubrious effect observed in this study might be due to the antioxidant and membrane stabilizing potential of diosgenin.
 ...
PMID:Antilipoperoxidative and membrane stabilizing effect of diosgenin, in experimentally induced myocardial infarction. 1923 76

Subsequent to myocardial infarction, cardiomyocytes within the infarcted areas and border zones expose phosphatidylserine (PS) in the outer plasma membrane leaflet (flip-flop). We showed earlier that in addition to apoptosis, this flip-flop can be reversible in cardiomyocytes. We now investigated a possible role for Rho and downstream effector Rho-associated kinase (ROCK) in the process of (reversible) PS exposure and apoptosis in cardiomyocytes. In rat cardiomyoblasts (H9c2 cells) and isolated adult ventricular rat cardiomyocytes Clostridium difficile Toxin B (TcdB), a Rho GTPase family inhibitor, C3 transferase (C3), a Rho(A,B,C) inhibitor and the ROCK inhibitors Y27632 and H1152 were used to inhibit Rho-ROCK signaling. PS exposure was assessed via flow cytometry and fluorescent digital imaging microscopy using annexin V. Akt expression and phosphorylation were analyzed via Western blot, and Akt activity was inhibited by wortmannin. The cellular concentration activated caspase 3 was determined as a measure of apoptosis, and flippase activity was assessed via flow cytometry using NBD-labeled PS. TcdB, C3, Y27632 and H1152 all significantly increased PS exposure. TcdB, Y27632 and H1152 all significantly inhibited phosphorylation of the anti-apoptotic protein Akt and Akt inhibition by wortmannin lead to increased PS exposure. However, only TcdB and C3, but not ROCK- or Akt inhibition led to caspase 3 activation and thus apoptosis. Notably, pancaspase inhibitor zVAD only partially inhibited TcdB-induced PS exposure indicating the existence of apoptotic and non-apoptotic PS exposure. The induced PS exposure coincided with decreased flippase activity as measured with NBD-labeled PS flip-flop. In this study, we show a regulatory role for a novel signaling route, Rho-ROCK-flippase signaling, in maintaining asymmetrical membrane phospholipid distribution in cardiomyocytes.
 ...
PMID:Inhibition of Rho-ROCK signaling induces apoptotic and non-apoptotic PS exposure in cardiomyocytes via inhibition of flippase. 2069 98

Lipid transport is an essential process with manifest importance to human health and disease. Phospholipid flippases (P4-ATPases) transport lipids across the membrane bilayer and are involved in signal transduction, cell division, and vesicular transport. Mutations in flippase genes cause or contribute to a host of diseases, such as cholestasis, neurological deficits, immunological dysfunction, and metabolic disorders. Genome-wide association studies have shown that ATP10A and ATP10D variants are associated with an increased risk of diabetes, obesity, myocardial infarction, and atherosclerosis. Moreover, ATP10D SNPs are associated with elevated levels of glucosylceramide (GlcCer) in plasma from diverse European populations. Although sphingolipids strongly contribute to metabolic disease, little is known about how GlcCer is transported across cell membranes. Here, we identify a conserved clade of P4-ATPases from Saccharomyces cerevisiae (Dnf1, Dnf2), Schizosaccharomyces pombe (Dnf2), and Homo sapiens (ATP10A, ATP10D) that transport GlcCer bearing an sn2 acyl-linked fluorescent tag. Further, we establish structural determinants necessary for recognition of this sphingolipid substrate. Using enzyme chimeras and site-directed mutagenesis, we observed that residues in transmembrane (TM) segments 1, 4, and 6 contribute to GlcCer selection, with a conserved glutamine in the center of TM4 playing an essential role. Our molecular observations help refine models for substrate translocation by P4-ATPases, clarify the relationship between these flippases and human disease, and have fundamental implications for membrane organization and sphingolipid homeostasis.
 ...
PMID:Yeast and human P4-ATPases transport glycosphingolipids using conserved structural motifs. 3053 Apr 92