Amoxapine Inhibits Delayed Outward Rectifier K+ Currents in Cerebellar Granule Cells via Dopamine Receptor and Protein Kinase A Activation

Cellular Physiology and Biochemistry

关键词: Amoxapine;    IK;    PKA;    Cerebellar granule neuron;    D1-like receptor;   

DOI  :  10.1159/000331725

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background Although tricyclic antidepressants amoxapine is proposed to target 5-HT and D2 receptors, very few studies have addressed the effect of amoxapine on molecular and cellular mechanisms via receptor pathways. In this study, we test the effect of amoxapine on rat cerebellar granule neurons (CGNs) to address this possibility. Methods CGNs cell culture, whole-cell current recording using a patch-clamp technique, western blot and non-radioactive detection analysis of phosphorylated protein kinase A (PKA) were used. Results Amoxapine inhibits delayed rectifier potassium (I_K) current in a dose-dependent manner and modulates inactivation properties in CGNs. Those effects were not eliminated by preincubation with 5-HT or 5-HT receptor antagonists, but abolished by dopamine and D1/D5 receptor antagonists. Application of GTPγ-S and inhibitor of the Gs signalling cascade abolished the amoxapine-induced effect on I_K. The application of forskolin or dibutyryl-cAMP mimicked the inhibitory effect of amoxapine on I_K. Western blotting for phosphorylated PKA revealed that amoxapine significantly increased the intracellular levels of phosphorylated PKA, a marker of PKA activation. Conclusion Amoxapine inhibits I_K currents in rat CGNs via cAMP/PKA-dependent pathways, as in mouse cortical neurons we reported earlier, but that involves D1-like receptors instead of 5-HT receptors.

【 授权许可】

CC BY-NC-ND