Amoxapine inhibits the delayed rectifier outward K+ current in mouse cortical neurons via cAMP/protein kinase A pathways

The Journal of Pharmacology and Experimental Therapeutics
Yan-Lin HeYan-Ai Mei

Abstract

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 ...Continue Reading

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Citations

Sep 29, 2011·Journal of Neuroscience Research·Xiao-Qin ZhanYan-Ai Mei
Aug 26, 2011·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Guang YangYan-Ai Mei
Dec 3, 2013·Therapeutic Advances in Psychopharmacology·Kevin C ReevesAnne-Marie Duchemin
Dec 14, 2011·Psychopharmacology·Chin-Wei HuangSheng-Nan Wu
Jan 22, 2015·Journal of Natural Products·Tiago dos Santos-NascimentoJosé Henrique Leal-Cardoso

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