title: Cyproheptadine enhances the I(K) of mouse cortical neurons through sigma-1 receptor-mediated intracellular signal pathway.
abstract: Cyproheptadine (CPH) is a histamine- and serotonin-receptor antagonist, and its effects are observed recently in the modulation of multiple intracellular signals. In this study, we used cortical neurons and HEK-293 cells transfected with Kv2.1 α-subunit to address whether CPH modify neural voltage-gated K(+) channels by a mechanism independent of its serotonergic and histaminergic properties. Our results demonstrate that intracellularly delivered CPH increased the I(K) by reducing the activity of protein kinas A (PKA). Inhibition of G(i) eliminated the CPH-induced effect on both the I(K) and PKA. Blocking of 5-HT-, M-, D(2)-, H(1)- or H(2)-type GPCR receptors with relevant antagonists did not eliminate the CPH-induced effect on the I(K). Antagonists of the sigma-1 receptor, however, blocked the effect of CPH. Moreover, the inhibition of sigma-1 by siRNA knockdown significantly reduced the CPH-induced effect on the I(K). On the contrary, sigma-1 receptor agonist mimicked the effects of CPH on the induction of I(K). A ligand-receptor binding assay indicated that CPH bound to the sigma-1 receptor. Similar effect of CPH were obtained from HEK-293 cells transfected with the α-subunit of Kv2.1. In overall, we reveal for the first time that CPH enhances the I(K) by modulating activity of PKA, and that the associated activation of the sigma-1 receptor/G(i)-protein pathway might be involved. Our findings illustrate an uncharacterized effect of CPH on neuron excitability through the I(K), which is independent of histamine H(1) and serotonin receptors.
authors: Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors: Yan-Lin
authors: YL
authors: He
authors: Chun-Lei
authors: CL
authors: Zhang
authors: Xiao-Fei
authors: XF
authors: Gao
authors: Jin-Jing
authors: JJ
authors: Yao
authors: Chang-Long
authors: CL
authors: Hu
authors: Yan-Ai
authors: YA
authors: Mei
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003533:Cyproheptadine / Q000494:pharmacology*; D004553:Electric Conductivity; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D051669:Shab Potassium Channels / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000097605:Sigma-1 Receptor
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003533:Cyproheptadine; D006633:Histamine Antagonists; D011188:Potassium; D017480:Receptors, sigma; D051669:Shab Potassium Channels; D000097605:Sigma-1 Receptor