Amoxapine inhibits the delayed rectifier outward K+ current in mouse cortical neurons via cAMP/protein kinase A pathways.
Ion channels are known to be modulated by antidepressant drugs, but the molecular mechanisms are not known. We have shown that the antidepressant drug amoxapine suppresses rectifier outward K(+) (I(K)) currents in mouse cortical neurons. At a concentration of 10 to 500 muM, amoxapine reversibly inhibited I(K) in a dose-dependent manner and modulated both steady-state activation and inactivation properties. The application of forskolin or dibutyryl cAMP mimicked the inhibitory effect of amoxapine on I(K) and abolished further inhibition by amoxapine. N-[2-(p-Bromocinnamylamino)ethyl]-5-iso-quinolinesulphonamide (H-89), a protein kinase A (PKA) inhibitor, augmented I(K) amplitudes and completely eliminated amoxapine inhibition of I(K). Amoxapine was also found to significantly increase intracellular cAMP levels. The effects of amoxapine on I(K) were abolished by preincubation with 5-hydroxytryptamine (5-HT) and the antagonists of 5-HT(2) receptor. Moreover, intracellular application of guanosine 5'-[gammathio]-triphosphate increased I(K) amplitudes and prevented amoxapine-induced inhibition. The selective Kv2.1 subunit blocker Jingzhaotoxin-III reduced I(K) amplitudes by 30% and also significantly abolished the inhibitory effect of amoxapine. Together these results suggest that amoxapine inhibits I(K) in mouse cortical neurons by cAMP/PKA-dependent pathway associated with the 5-HT receptor, and suggest that the Kv2.1 alpha-subunit may be the target for this inhibition.
He
Yan-Lin
YL
nstitutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
Zhan
Xiao-Qin
XQ
Yang
Guang
G
Sun
Ji
J
Mei
Yan-Ai
YA
D000657:Amoxapine / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects*; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D051669:Shab Potassium Channels / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
D018687:Antidepressive Agents, Second-Generation; D051668:Delayed Rectifier Potassium Channels; D058830:Serotonin 5-HT2 Receptor Antagonists; D051669:Shab Potassium Channels; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000657:Amoxapine