ATM (ataxia-telangiectasia mutated) is activated by a variety of noxious agent, including oxidative stress, and ATM deficiency results in an anomalous cellular response to oxidative stress. However, the mechanisms for ATM activation by oxidative stress remain to be established. Furthermore, it is not clear whether ATM responds to oxidative DNA damage or to a change in the intracellular redox state, independent of DNA damage. We found that ATM is activated by N -methyl-N ′ ′ ′ ′ -nitronitrosoguanidine (MNNG) and 15-deoxy-∆ ∆ ∆ ∆ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), in NBS1 -or MSH6 -deficient cells. We further found that ATM is activated by treating chromatin-free immunoprecipitated ATM with MNNG or 15d-PGJ 2 , which modifies free sulfhydryl (SH) groups, and that 15d-PGJ 2 binds covalently to ATM. Interestingly, 15d-PGJ 2 -induced ATM activation leads to p53 activation and apoptosis, but not to Chk2 or H2AX phosphorylation. These results indicate that ATM is activated through the direct modification of its SH groups, independent of DNA damage, and this activation leads, downstream, to apoptosis.

In this study, we have investigated the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on in vitro hamster submandibular ganglion neurons using the conventional intracellular recording technique. PACAP (10M) induced slow depolarizations in approximately 70% of tested cells. PACAP-induced depolarizations were approximately 10mV in the peak amplitude, and their durations were approximately 10 min. The slow depolarizations were accompanied by a decrease in membrane conductance (g m ) at the initial phase and an increase in g m at the peak phase. Membrane input resistance increased by ‫%2.2ע8.41‬ (mean‫ע‬S.E., max.) of the resting value at the initial phase and decreased by ‫%3.4ע8.03‬ (max.) at the peak phase. Anodal break spikes were elicited at the initial phase during PACAP-induced depolarization. In one neuron, anodal break spikes were elicited at the peak. Spikes which followed the anodal break spike were also elicited at 4Hz in the initial phase during the slow depolarizations. The decrease in g m was probably produced by an inhibition of calcium conductance and an inhibition of slow Ca ‫ם2‬-activated K ‫ם‬ channels, while the increase in g m might have been produced by an activation of nonselective cation channels. The slow depolarizations by PACAP might be mediated by a membrane-delimited signal transduction cascade involving G protein in the submandibular ganglion neurons.

An investigation of the Ammon's horn seizure with macro-electrodes has been conducted in our department by Harafuji6) and Oka7>. But in the experiments using macro-electrodes, there is a limit to the analysis of wave pattern and it is impossible to isolate neuronal elements which participate in the development of seizure. Therefore, the present study was designed to use micro-electrodes in order to investigate the activity of neuronal elements at the time of seizure and thus to make clear the arising mechanism of the seizure discharge').