K+-ATP-channel-related protein complexes: potential transducers in the regulation of epithelial tight junction permeability

Abstract

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.