title: The antidepressant citalopram inhibits delayed rectifier outward K⁺ current in mouse cortical neurons.
abstract: Citalopram, a selective serotonin (5-HT) reuptake inhibitor (SSRI) as well as an antidepressant, is thought to exert its effects by increasing synaptic 5-HT levels. However, few studies have addressed the possibility that citalopram has other molecular mechanisms of action. We examined the effects of citalopram on delayed rectifier outward K(+) current (I(K) ) in mouse cortical neurons. Extracellular citalopram reversibly inhibited I(K) in a dose-dependent manner and significantly shifted both steady-state activation and inactivation curves toward hyperpolarization. Neither 5-HT itself nor antagonists of 5-HT and dopamine receptors could abolish citalopram-induced inhibition of I(K) . In addition, intracellular application of GTPγ-S similarly failed to prevent the inhibition of I(K) by citalopram. When applied intracellularly, citalopram had no effect on I(K) and did not influence the reduction of I(K) induced by extracellular citalopram. The effect of citalopram was use dependent, but not frequency dependent, and it did not require channel opening. Electrophysiological recordings in acute cortical slice showed that citalopram significantly reduced the action potential (AP) firing frequency of cortical neurons and increased action potential duration (APD). The selective Kv2.1 subunit blocker Jingzhaotoxin-III (JZTX-III) did not abolish citalopram-induced I(K) inhibition. Transfection of HEK293 cells with Kv2.1 or Kv2.2 constructs indicated that citalopram mainly inhibited Kv2.2 current. We suggest that citalopram-induced inhibition of I(K) in mouse cortical neurons is independent of G-protein-coupled receptors and might exert its antidepressant effects by enhancing presynaptic efficiency. Our results may help to explain some of the unknown therapeutic effects of citalopram.
authors.affiliation: Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Zhan
authors.forename: Yan-Lin
authors.initials: YL
authors.lastname: He
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Yao
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Zhuang
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D001703:Biophysics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013111:Spider Venoms / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D000928:Antidepressive Agents; D010455:Peptides; D051669:Shab Potassium Channels; D013111:Spider Venoms; C487820:jingzhaotoxin-III, Chilobrachys jingzhao; D015283:Citalopram