title: Regulation of membrane KCNQ1/KCNE1 channel density by sphingomyelin synthase 1.
abstract: Sphingomyelin synthase (SMS) catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and diacylglycerol. We previously showed that SMS1 deficiency leads to a reduction in expression of the K(+) channel KCNQ1 in the inner ear (Lu MH, Takemoto M, Watanabe K, Luo H, Nishimura M, Yano M, Tomimoto H, Okazaki T, Oike Y, and Song WJ. J Physiol 590: 4029-4044, 2012), causing hearing loss. However, it remains unknown whether this change in expression is attributable to a cellular process or a systemic effect in the knockout animal. Here, we examined whether manipulation of SMS1 activity affects KCNQ1/KCNE1 currents in individual cells. To this end, we expressed the KCNQ1/KCNE1 channel in human embryonic kidney 293T cells and evaluated the effect of SMS1 manipulations on the channel using whole cell recording. Application of tricyclodecan-9-yl-xanthogenate, a nonspecific inhibitor of SMSs, significantly reduced current density and altered channel voltage dependence. Knockdown of SMS1 by a short hairpin RNA, however, reduced current density alone. Consistent with this, overexpression of SMS1 increased the current density without changing channel properties. Furthermore, application of protein kinase D inhibitors also suppressed current density without changing channel properties; this effect was nonadditive with that of SMS1 short hairpin RNA. These results suggest that SMS1 positively regulates KCNQ1/KCNE1 channel density in a protein kinase D-dependent manner.
authors.affiliation: Department of Sensory and Cognitive Physiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Program for Leading Graduate Schools HIGO Program, Kumamoto University, Kumamoto, Japan;
authors.forename: Meikui
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Sensory and Cognitive Physiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;
authors.forename: Makoto
authors.initials: M
authors.lastname: Takemoto
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan;
authors.forename: Makoto
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: RIKEN Brain Science Institute, Wako, Japan; and.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan; Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: Department of Sensory and Cognitive Physiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Program for Leading Graduate Schools HIGO Program, Kumamoto University, Kumamoto, Japan; song@kumamoto-u.ac.jp.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Song
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D024642:Potassium Channels, Voltage-Gated; C089212:protein kinase D; D011493:Protein Kinase C; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups); D011188:Potassium
keywords: KCNE1; KCNQ1; PKD; sphingomyelin synthase