title: Inhibitory effect of polycations on phosphorylation of glycogen synthase by glycogen synthase kinase 3.
abstract: Several polycations were tested for their abilities to inhibit the activity of glycogen synthase kinase 3 (GSK-3). L-Polylysine was the most powerful inhibitor of GSK-3 with half-maximal inhibition of glycogen synthase phosphorylation occurring at approx. 100 nM. D-Polylysine and histone H1 were also inhibitory, but the concentration dependence was complex, and DL-polylysine was the least effective inhibitor. Spermine caused about 50% inhibition of GSK-3 at 0.7 mM and 70% inhibition at 4 mM. Inhibition of GSK-3 by L-polylysine could be blocked or reversed by heparin. A heat-stable polycation antagonist isolated from swine kidney cortex also blocked the inhibitory effect of L-polylysine on GSK-3 and blocked histone H1 stimulation of protein phosphatase 2A activity. Under the conditions tested, L-polylysine also inhibited GSK-3 catalyzed phosphorylation of type II regulatory subunit of cAMP-dependent protein kinase and a 63 kDa brain protein, but only slightly inhibited phosphorylation of inhibitor 2 or proteolytic fragments of glycogen synthase that contain site 3 (a + b + c). L-Polylysine at a concentration (200 nM) that caused nearly complete inhibition of GSK-3 stimulated casein kinase I and casein kinase II, but had virtually no effect on the catalytic subunit of cAMP-dependent protein kinase. These results suggest that polycations can be useful in controlling GSK-3 activity. Polycations have the potential to decrease the phosphorylation state of glycogen synthase at site 3, both by inhibiting GKS-3 as shown in this study and by stimulating the phosphatase reaction as shown previously (Pelech, S. and Cohen, P. (1985) Eur. J. Biochem. 148, 245-251).
authors.affiliation: Department of Biochemistry, Medical College of Ohio, Toledo 43699.
authors.forename: M G
authors.initials: MG
authors.lastname: Hegazy
authors.forename: K K
authors.initials: KK
authors.lastname: Schlender
authors.forename: S E
authors.initials: SE
authors.lastname: Wilson
authors.forename: E M
authors.initials: EM
authors.lastname: Reimann
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006006:Glycogen Synthase / Q000378:metabolism*; D038341:Glycogen Synthase Kinases; D010766:Phosphorylation; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors
chemical_list: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006006:Glycogen Synthase; D038341:Glycogen Synthase Kinases; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers; D047428:Protein Kinase Inhibitors