Multivalent ganglioside and sphingosine conjugates modulate myelin protein kinases.
Gangliosides, added exogenously at concentrations of 10-100 microM, inhibit intrinsic protein kinase activities in purified rat brain myelin. Multivalent neoganglioproteins--gangliosides covalently attached, via their lipid moieties, to bovine serum albumin--were much more potent, inhibiting myelin protein phosphorylation half-maximally at a concentration of 100 nM. Different ganglioside conjugates varied 10-fold in inhibitory potency; GT1b-conjugates being the most potent and GM3-conjugates being the least. Conjugates of ganglioside oligosaccharides, lacking the lipid moiety, did not inhibit myelin protein phosphorylation, whereas conjugates of sphingosine inhibited nearly as potently as GT1b conjugates. Conjugate-mediated inhibition of myelin protein phosphorylation was due to inhibition of a protein serine kinase activity rather than activation of a phosphatase activity. We conclude that (i) clustered gangliosides or sphingosine are potent myelin protein kinase inhibitors, and (ii) sphingolipid metabolism is not required for myelin protein kinase inhibition. In contrast to their effects on myelin protein phosphorylation, ganglioside conjugates stimulated phosphorylation of a presumptive axon membrane protein. The data support the conclusion that gangliosides and other sphingolipids, when appropriately clustered, are potent modulators of central nervous system protein phosphorylation.
Mahoney
J A
JA
Department of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Schnaar
R L
RL
D000818:Animals; D001921:Brain / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D005732:Gangliosides / Q000138:chemical synthesis / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000138:chemical synthesis / Q000494:pharmacology*; D013107:Sphingolipids / Q000138:chemical synthesis / Q000494:pharmacology*
D005732:Gangliosides; D009419:Nerve Tissue Proteins; D013107:Sphingolipids; C058397:ganglioside GT1b-bovine serum albumin complex; D012710:Serum Albumin, Bovine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3