K+-ATP-channel-related protein complexes: potential transducers in the regulation of epithelial tight junction permeability.
K(+)-ATP channels are composed of an inwardly rectifying Kir6 subunit and an auxiliary sulfonylurea receptor (SUR) protein. The SUR subunits of Kir6 channels have been recognized as an ATPase, which appears to work as a mechanochemical device like other members of the ABC protein family. Thus, in spite of just gating ions, Kir6/Sur might, in addition, regulate completely different cellular systems. However, so far no model system was available to directly investigate this possibility. Using highly specific antibodies against Kir6.1-SUR2A and an in vitro model system of the rat small intestine, we describe a new function of the Kir6.1-SUR2A complex, namely the regulation of paracellular permeability. The Kir6.1-SUR2A complex localizes to regulated tight junctions in a variety of gastrointestinal, renal and liver tissues of rat, pig and human, whereas it is absent in the urothelium. Changes in paracellular permeability following food intake was investigated by incubating the lumen of morphological well-defined segments of rat small intestine with various amounts of glucose. Variations in the lumenal glucose concentrations and regulators of Kir6.1/SUR2A activity, such as tolbutamide or diazoxide, specifically modulate paracellular permeability. The data presented here shed new light on the physiological and pathophysiological role K(+)-ATP channels might have for the regulation of tight junctions.
Jöns
Thomas
T
Charité-Universitätsmedizin Berlin, Centrum für Anatomie, Institut für Integrative Neuroanatomie, Philippstr. 12, 10115 Berlin, Germany. thomas.joens@charite.de
Wittschieber
Daniel
D
Beyer
Anja
A
Meier
Carola
C
Brune
Andreas
A
Thomzig
Achim
A
Ahnert-Hilger
Gudrun
G
Veh
Rüdiger W
RW
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004435:Eating; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D062793:Occludin; D010539:Permeability / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D064233:Sulfonylurea Receptors; D013552:Swine; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D014044:Tolbutamide / Q000494:pharmacology; D019459:Urothelium / Q000166:cytology / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D000959:Antihypertensive Agents; D007004:Hypoglycemic Agents; D054086:KATP Channels; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C568985:OCLN protein, human; D062793:Occludin; C568987:Ocln protein, rat; D010750:Phosphoproteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C092520:uK-ATP-1 potassium channel; D014044:Tolbutamide; D003981:Diazoxide