INHIBITION OF THE ATP-SENSITIVE POTASSIUM CHANNEL FROM MOUSE PANCREATIC BETA-CELLS BY SURFACTANTS

1 We have used patch-clamp methods to study the effects of the deterge nts, Cremophor, Tween 80 and Triton X100 on the K-ATP channel in the p ancreatic beta-cell from mouse. 2 All three detergents blocked K-ATP c hannel activity with the following order of potency: Tween 80 (K-i < s imilar to 83 nM) > Triton X100 (K-i = 350 nM) > Cremophor. In all case s the block was poorly reversible. 3 Single-channel studies suggested that at low doses, the detergents act as slow blockers of the K-ATP ch annel. 4 Unlike the block produced by tolbutamide, that produced by de tergent was not affected by intracellular Mg2+-nucleotide, diazoxide o r trypsin treatment, nor did it involve an acceleration of rundown or increase in ATP sensitivity of the chanel. 5 The detergents could bloc k the pore-forming subunit, Kir6.2 Delta C26, which can be expressed i ndependently of SUR1 (the regulatory subunit of the K-ATP channel). Th ese data suggest that the detergents act on Kir6.2 and not SUR1. 6 The detergents had no effect on another member of the inward rectifier fa mily: Kir1.1a (ROMK1). 7 Voltage-dependent K-currents in the beta-cell were reversibly blocked by the detergents with a far lower potency th an that found for the K-ATP channel. 8 Like other insulin secretagogue s that act by blocking the K-ATP channel, Cremophor elevated intracell ular Ca2+ in single beta-cells to levels that would be expected to eli cit insulin secretion. 9 Given the role of the K-ATP channel in many p hysiological processes, we conclude that plasma borne detergent may ha ve pharmacological actions mediated through blockage of the K-ATP chan nel.