Modulation of phospholipase C pathway in rat cerebral cortex during aging.
The regulation of the alpha(1)-adrenoceptor-G protein-phospholipase C (PLC) cascade was investigated in rat cerebral cortex at adult (6-month-old) and senescent (24-month-old). Norepinephrine (NE)-stimulated inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] production was enhanced 30% during aging. Moreover, maximal NE (50 microM) stimulation was much more effective in stimulating G protein low-K(m) GTPase in cortical membranes from old than adult rats. Immunoreactive G protein subunits (Gqalpha, Gialpha, Goalpha and Gcommonbeta) and PLC-beta(1) isozyme were detected in all membrane preparations. No changes in the G protein subunits and PLC-beta(1) expression were observed with aging. Nanomolar concentration of Gpp[NH]p inhibited basal Ins(1,4,5)P(3) production with a maximum inhibition of 25% in both adult and aged cortical membranes. In contrast, 100 microM Gpp[NH]p-induced stimulation of Ins(1,4,5)P(3) production was potentiated with aging. The two principal divergent pathways of old cortical Ins(1,4,5)P(3) production resulting in the activation and inhibition of PLC-beta(1) activity are abolished by treatment of the membranes with 1 microM U-73122, a putative PLC-beta inhibitor. These results suggest that the cortical PLC-beta(1) isozyme activity may be regulated by both inhibitory and stimulatory G proteins-mediated mechanisms, and that the altered PLC-beta(1) dual regulatory systems could be involved in the pathogenesis of brain aging.
Miyamoto
A
A
Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Chuo-ku, Japan. atsushi@sapmed.ac.jp
Ohshika
H
H
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D054799:Phospholipase C beta; D021122:Protein Subunits; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D010738:Type C Phospholipases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004963:Estrenes; D007527:Isoenzymes; D021122:Protein Subunits; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D006165:Guanylyl Imidodiphosphate; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins