Phorbol esters inhibit agonist-induced [³H] inositol-1-phosphate accumulation in rat hippocampal slices

In rat hippocampal slices, carbachol and norepinephrine induce an accumulation of [³H]-inositol-1-phosphate which is markedly amplified in the presence of lithium. The tumor-promoting agents phorbol 12, 13-dibutyrate (PDB) and 4β phorbol, 12β-myristate, 13 α-acetate (PMA) have no effect on [³H] inositol-1-phophate accumulation alone, but when preincubated with hippocampal slices significantly inhibit the accumulation of [³H]-inositol-1-phosphate induced by carbachol and norepinephrine. The IC₅₀ values for PDB and PMA are 0.2μM and 25μM respectively. In contrast, the weak tumor promoting agents 4-O-methylphorbol 12 myristate 13 acetate (MPMA) and phorbol 13,20-diacetate (P 13,20 DA) only slightly attenuate the agonist-induced response at concentrations ≤100μM, whereas 4α-phorbol (4α-PHR), a biologically inactive phorbol, has no effect. These data suggest that phorbol ester receptor-mediated events may be negatively coupled to agonist-induced phosphatidylinositol hydrolysis.