title: KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability.
abstract: Na(+)-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K(+) channel β subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2(-/-) mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na(+)-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but was inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K(+) channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activities of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1 but were suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.
authors.affiliation: 1Bioelectricity Laboratory, Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
authors.forename: Kwok-Keung
authors.initials: KK
authors.lastname: Tai
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Neverisky
authors.forename: Alex
authors.initials: A
authors.lastname: Hansler
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.forename: Torsten K
authors.initials: TK
authors.lastname: Roepke
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lerner
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Bojana
authors.initials: B
authors.lastname: Zupan
authors.forename: Miklos
authors.initials: M
authors.lastname: Toth
authors.forename: Robin
authors.initials: R
authors.lastname: Haynes
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Huang
authors.forename: Didem
authors.initials: D
authors.lastname: Demirbas
authors.forename: Roberto
authors.initials: R
authors.lastname: Buccafusca
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.forename: Vikram A
authors.initials: VA
authors.lastname: Kanda
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
mesh_terms: D000818:Animals; D016466:CHO Cells; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D007294:Inositol / Q000097:blood; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D013058:Mass Spectrometry; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D046912:Multiprotein Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D051657:KCNQ1 Potassium Channel; C489620:Kcne2 protein, mouse; C496910:Kcnq1 protein, mouse; D046912:Multiprotein Complexes; D024642:Potassium Channels, Voltage-Gated; C508355:SLC5A3 protein, mouse; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D027981:Symporters; D007294:Inositol