Regulation of the phosphoinositide cascade by polyamines in brain.
The endogenous polyamines spermidine and spermine enhanced guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S)-stimulated phosphoinositide turnover with EC50 values of 100 +/- 30 and 50 +/- 15 microM, respectively, whereas the synthetic polyamines N,N'-bis(3-aminopropyl)-1,3-propanediamine and -ethylenediamine inhibited GTP-gamma-S-stimulated phosphoinositide turnover, with maximal inhibition at 1 mM. Kinetic analysis of GTP-gamma-S-stimulated phosphoinositide turnover in the absence and presence of spermidine showed that the Km for GTP-gamma-S was not changed (1,303 +/- 270 and 1,069 +/- 214 nM, respectively), whereas the Vmax was increased by 206% (1,566 +/- 141 and 4,792 +/- 84 cpm, respectively), indicating that spermidine and GTP-gamma-S acted at different sites. Spermidine also enhanced Ca(2+)-stimulated phosphoinositide turnover in the absence of GTP-gamma-S by decreasing the Ca2+ requirement of the phosphoinositide-specific phospholipase C. Arcaine and agmatine, polyamine antagonists at the NMDA receptor complex, did not block the effects of spermidine on GTP-gamma-S- and Ca(2+)-induced phosphoinositide turnover, suggesting that the spermidine effects are not mediated through these specific polyamine sites. Furthermore, spermidine increased the level of [3H]phosphatidylinositol 4-phosphate (EC50 = 120 +/- 10 microM), without affecting significantly the levels of [3H]-phosphatidylinositol and [3H]phosphatidylinositol 4,5-bis-phosphate. Collectively these data indicate that the enhanced phosphoinositide turnover induced by spermidine in the presence of GTP-gamma-S or Ca2+ is mediated through multiple levels of the phosphoinositide turnover cascade.
Periyasamy
S
S
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606.
Kothapalli
M R
MR
Hoss
W
W
D000376:Agmatine / Q000494:pharmacology; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology*; D006706:Homeostasis; D007700:Kinetics; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D013095:Spermidine / Q000494:pharmacology / Q000502:physiology; D013096:Spermine / Q000494:pharmacology / Q000502:physiology
D001645:Biguanides; D010716:Phosphatidylinositols; D011073:Polyamines; D003840:Deoxycholic Acid; C005391:diethylenetriamine; D013096:Spermine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C006624:arcaine; D000376:Agmatine; D002118:Calcium; D013095:Spermidine