KCNQ1, KCNE2, and Na(+)-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability

Item Type:	Article
Title:	KCNQ1, KCNE2, and Na(+)-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability
Creators Name:	Abbott, G.W and Tai, K.K. and Neverisky, D.L. and Hansler, A. and Hu, Z. and Roepke, T.K. and Lerner, D.J. and Chen, Q. and Liu, L. and Zupan, B. and Toth, M. and Haynes, R. and Huang, X. and Demirbas, D. and Buccafusca, R. and Gross, S.S. and Kanda, V.A. and Berry, G.T.
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 {beta} 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 {alpha} 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.
Keywords:	CHO Cells, Cerebrospinal Fluid, Choroid Plexus, Electron Microscopy, Fluorescent Antibody Technique, High Pressure Liquid Chromatography, Immunoprecipitation, Inositol, KCNQ1 Potassium Channel, Mass Spectrometry, Metabolome, Multiprotein Complexes, Neurons, Oocytes, Patch-Clamp Techniques, Sodium-Glucose Transporter 1, Symporters, Voltage-Gated Potassium Channels, Animals, Cricetinae, Cricetulus, Mice, Xenopus laevis
Source:	Science Signaling
ISSN:	1945-0877
Publisher:	American Association for the Advancement of Science
Volume:	7
Number:	315
Page Range:	ra22
Date:	4 March 2014
Official Publication:	https://doi.org/10.1126/scisignal.2005025
PubMed:	View item in PubMed

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