Mislocalization of K+ channels causes the renal salt wasting in EAST/SeSAME syndrome

• Published in: FEBS letters Vol. 588; no. 6; pp. 899 - 905
• Main Authors: Tanemoto, Masayuki, Abe, Takaaki, Uchida, Shunya, Kawahara, Katsumasa
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 18.03.2014
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Cell Adhesion Molecules; Cell Adhesion Molecules, Neuronal - metabolism; Cell Polarity; DCT; distal convoluted tubule; Dogs; EAST/SeSAME syndrome; Epithelial sodium transport; GFP; green fluorescent protein; Guanylate Kinases; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - metabolism; HEK; HEK293 Cells; human embryonic kidney; Humans; Intellectual Disability - genetics; Intellectual Disability - metabolism; Intracellular trafficking; inwardly rectifying K+ channel; Kidney; Kidney Tubules, Distal - metabolism; Kir; Madin Darby Canine Kidney Cells; Madin-Darby canine kidney; MAGI-1; MDCK; membrane-associated guanylate kinase with inverted domain structure-1; Mutation, Missense; Na+–Cl− cotransporter; NCC; peroxidase; Potassium channel; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Protein Transport; Seizures - genetics; Seizures - metabolism; Tubulopathy; MAGI-1; Epithelial sodium transport; Tubulopathy; Kidney; HEK; NCC; GFP; EAST/SeSAME syndrome; DCT; Kir; Intracellular trafficking; MDCK; Potassium channel; PO
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2014.02.024

•Kir4.1/Kir5.1 heteromers form basolateral K+ channels in renal distal tubules.•MAGI-1 facilitates K+-channel formation via interaction with Kir4.1.•Kir4.1 A167V mutant cannot interact with MAGI-1 in tubular cells.•Mistrafficking of mutant Kir4.1 inhibits its interaction with MAGI-1.•Mislocalization of K+ channel causes renal salt wasting in EAST/SeSAME syndrome. The Kir4.1/Kir5.1 channel mediates basolateral K+ recycling in renal distal tubules; this process is critical for Na+ reabsorption at the tubules. Mutations in Kir4.1 are associated with EAST/SeSAME syndrome, a genetic disorder characterized by renal salt wasting. In this study, we found that MAGI-1 anchors Kir4.1 channels (Kir4.1 homomer and Kir4.1/Kir5.1 heteromer) and contributes to basolateral K+ recycling. The Kir4.1 A167V mutation associated with EAST/SeSAME syndrome caused mistrafficking of the mutant channels and inhibited their expression on the basolateral surface of tubular cells. These findings suggest mislocalization of the Kir4.1 channels contributes to renal salt wasting. Kir5.1 and Kir4.1colocalize by fluorescence microscopy (View interaction) MAGI-1physically interacts with Kir4.1 by anti bait coimmunoprecipitation (View interaction) MAGI-1physically interacts with Kir4.1 by anti bait coimmunoprecipitation (1, 2) MAGI-1physically interacts with Kir4.1 by pull down (View interaction) Kir5.1physically interacts with Kir4.1 by anti bait coimmunoprecipitation (View interaction)