Modulation of phospholipase C pathway in rat cerebral cortex during aging

Abstract

The regulation of the α 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 μM) 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 (Gqα, Giα, Goα and Gcommonβ) and PLC-β 1 isozyme were detected in all membrane preparations. No changes in the G protein subunits and PLC-β 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 μM 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-β 1 activity are abolished by treatment of the membranes with 1 μM U-73122, a putative PLC-β inhibitor. These results suggest that the cortical PLC-β 1 isozyme activity may be regulated by both inhibitory and stimulatory G proteins-mediated mechanisms, and that the altered PLC-β 1 dual regulatory systems could be involved in the pathogenesis of brain aging.