| Title | Amoxapine inhibits the delayed rectifier outward K+ current in mouse cortical neurons via cAMP/PKA pathways. | | Author(s) | He YL, Zhan XQ, Yang G, Sun J, Mei YA | | Institution | Fudan University. | | Source | J Pharmacol Exp Ther 2009 Nov 13. | | Abstract | Ion channels are known to be modulated by antidepressant drugs, but the molecular mechanisms are not known. We have demonstrated that the antidepressant drug amoxapine suppresses rectifier outward K(+) (I(K)) currents in mouse cortical neurons. At a concentration of 10 muM 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 IK and abolished further inhibition by amoxapine. H-89, 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 pre-incubation with 5-HT and the antagonists of 5-HT(2) receptor. Moreover, intracellular application of GTPgamma-S increased I(K) amplitudes and prevented amoxapine-induced inhibition. The selective Kv2.1 subunit blocker Jingzhaotoxin-III (JZTX-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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19915071 |
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