Involvement of the delayed rectifier outward potassium channel Kv2.1 in methamphetamine-induced neuronal apoptosis via the p38 mitogen-activated protein kinase signaling pathway.

Methamphetamine (Meth) is an illicit psychostimulant with high abuse potential and severe neurotoxicity. Recent studies have shown that dysfunctions in learning and memory induced by Meth may partially reveal the mechanisms of neuronal channelopathies. Kv2.1, the primary delayed rectifying potassium channel in neurons, is responsible for mediating apoptotic current surge. However, whether Kv2.1 is involved in Meth-mediated neural injury remains unknown. In the present study, the treatment of primary cultured hippocampal neurons with Meth indicated that Meth induced a time- and dose-dependent augmentation of Kv2.1 protein expression, accompanied by elevated cleaved-caspase 3 and declined bcl-2/bax ratio. The blockage of Kv2.1 with the inhibitor GxTx-1E or the knockdown of the channel noticeably abrogated the pro-apoptotic effects mediated by Meth, demonstrating the specific roles of Kv2.1 in Meth-mediated neural damage. Additionally, the p38 mitogen-activated protein kinase (MAPK) signaling was demonstrated to be involved in Meth-mediated Kv2.1 upregulation and in the subsequent pro-apoptotic effects, as treatment with a p38 MAPK inhibitor significantly attenuated Meth-mediated Kv2.1 upregulation and cell apoptosis. Of note, PRE-084, a sigma-1 receptor agonist, obviously attenuated Meth-induced upregulation of Kv2.1 expression, neural apoptosis and p38 MAPK activation. Taken together, these results reveal a novel mechanism involved in Meth-induced neural death with implications for therapeutic interventions for Meth users.