Apolipoprotein E (apoE)-deficient (knockout) mice, 4 and 12 months old, were used to test if activation of the phosphoinositide signal transduction system coupled with muscarinic, adrenergic, or glutamatergic metabotropic receptors or inhibition by hydrogen peroxide or peroxynitrite was affected by apoE-deficiency in cerebral cortical slices. In 4-month-old apoE knockout mice, glutamatergic metabotropic receptor-stimulated phosphoinositide hydrolysis was 57% lower than age-matched wild-type mice, whereas the responses to muscarinic and adrenergic receptor stimulation were not different from wild-type mice. In 12-month-old mice, the response to glutamatergic metabotropic receptor stimulation remained impaired in apoE knockout mice, and an impairment in phosphoinositide hydrolysis activated by muscarinic receptors (36% decrease), but not by adrenergic receptors, also was evident. Oxidative stress induced by hydrogen peroxide or peroxynitrite inhibited phosphoinositide hydrolysis activated by muscarinic or glutamatergic metabotropic receptors equivalently (41 to 52%) in 4- and 12-month-old wild-type mice. In contrast, these oxidative agents had no effect on phosphoinositide hydrolysis activated by adrenergic receptors. The inhibitory effects of oxidative stress were not enhanced in apoE knockout mice. These results demonstrate that apoE-deficiency and oxidative stress have receptor-selective inhibitory effects on the phosphoinositide signal transduction system. These differential sensitivities to apoE and to oxidative stress may contribute to selective impairments in signaling activity in neurodegenerative conditions associated with apoE isoform-sensitivity or oxidative stress, such as Alzheimer's disease.