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

Abstract

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.

Sigma‐1 receptor activation‐induced glycolytic ATP production and endothelial barrier enhancement

“…To test the impact of σ1 activation on endothelial barrier function, we performed a concentration‐response study with the highly selective σ1 agonist, PRE‐084, at concentrations of 1, 5, 10, 50, 100, 150, and 200 μM, based on previously reported data 6,40‐42 . The results show a concentration‐dependent increase in barrier enhancement (Figure 1A,B).…”

Structural basis for σ1 receptor ligand recognition

“…A brief survey of the literature reveals that when using σ 1 receptor ligands in cellular or biochemical assays, incubation times and temperatures vary from room temperature for 20 minutes 37 to 37 °C incubation for up to 72 hours 35 . Ligand concentrations are sometimes nearly 10,000-fold over K d 38–40 . Our data indicate that it can take 1.5 hours or longer to reach saturation at 37 °C (Supplementary Fig.…”

Structural basis for σ1 receptor ligand recognition

“…A brief survey of the literature reveals that when using σ 1 receptor ligands in cellular or biochemical assays, incubation times and temperatures vary from room temperature for 20 minutes 33 to 37 °C incubation for up to 72 hours 31 . Ligand concentrations are sometimes nearly 10,000-fold over K d [34][35][36] . Our data indicate that it can take 1.5 hours or longer to reach saturation at 37 °C, and at room temperature it can take nearly a day.…”