Activation of ATP-sensitive K channels protects hippocampal CA1 neurons from hypoxia by suppressing p53 expression

Oxygen-sensing and responses to changes in oxygen concentration is a fundamental property of cellular physiology. In the central nervous system (CNS), hippocampal CA1 neurons are known to be extremely vulnerable to low oxygen concentrations or anoxia. Understanding the mechanisms governing tolerance to oxygen depletion is vital for developing strategies to protect the brain from hypoxic-ischemic insult. Our current study demonstrates the protective mechanism of KATP channels on hippocampal CA1 neurons subjected to hypoxic or anoxic conditions. Specifically, we show that CA1 neurons undergo apoptosis when depleted of oxygen for 12 or 24 h. A KATP channels agonist diazoxide inhibits the observed apoptosis. The inhibition of apoptosis is mediated through diazoxide's ability to reduce p53 expression. On the other hand, tolbutamide, a KATP channels antagonist which blocks the cellular sulphonylureas receptor, significantly increases p53 expression and apoptosis under hypoxic/anoxic conditions. Trichostatin (TSA), a p53 inhibitor, can block the effects of tolbutamide, lending further support for a role of p53 in mediating this process. These studies demonstrate that KATP channels act as an upstream antagonist of p53 in hippocampal CA1 neurons, and suggests their protective role in cerebral hypoxia.