Inhibition of the Na+,K+ pump by the epileptogenic pentylenetetrazole

Pentylenetetrazole (PTZ) is a convulsant drug used in animal experiments to induce epileptic activity. It is known to interact with a variety of channels and neurotransmitter receptors. We investigated the effects of PTZ on the Na+,K+ pump by measuring pump-mediated current, 86Rb+ uptake and [3H]ouabain binding using the Xenopus oocytes as a model system. PTZ inhibits Rb+ uptake with a KI value of about 10 mM, and the number of pump molecules is not altered as judged by the number of ouabain-binding sites. The measurements of pump current under voltage-clamp conditions revealed voltage-dependent inhibition with KI values increasing with depolarization. Reduced sensitivity to PTZ in the presence of ouabain and at reduced external K+ suggests that PTZ directly interacts with the transport ATPase and binds preferentially to the E1 form. Development of inhibition and recovery have time constants of about 10 min, which suggests that the externally applied PTZ acts on the pump from the cytoplasmic or membrane phase. Since inhibition of the Na+,K+ pump is accompanied by membrane depolarization, PTZ should promote the generation of discharges and contribute to the epileptogenic effects through pump inhibition.