European Journal of Pharmacology, 216 (1992) 323-326 323 © 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00 EJP 21077 Short communication 8-Metho~psoralen blocks ATP-sensitive potassium channels and stimulates insulin release Adam Szewczyk 1, Jan R. De Weille and Michel Lazdunski lnstitut de Pharmacologie Mol~culaire et Cellulaire, 660 Route des Lucioles, Sophia Antipolis 06560 Valbonne, France Received 3 February 1992, revised MS received 3 April 1992, accepted 16 April 1992 8-Methoxypsoralen (8-MOP) stimulated insulin release from HIT-T15 B-cells and inhibited the diazoxide-induced and sulfonylurea-sensitive 86Rb+ effiux from these cells. These results indicate that 8-MOP affects ATP-sensitive K + channel activity. Patch-clamp experiments confirmed this view. 8-Methoxypsoralen; K + channels (ATP-sensitive); Insulin release; B-cells 1. Introduction 8-Methoxypsoralen (8-MOP), a naturally occurring photoactive psoralen (furocoumarin), is an important therapeutic agent used to treat psoriasis, Vitiligo and cutaneous T-cell lymphoma (Parrish et al., 1974; An- derson and Voorhees, 1980). Various mechanisms have been proposed to explain the mode of action by which psoralens exert their photobiologic effects, and it is now generally accepted that their major target is DNA (see for example Averbeck, 1989). However 8-MOP has many other effects. 8-MOP is particularly well known as an inhibitor of arachidonic acid degradation by cytochrome P450 monooxygenase (Mays et al., 1990). It is because we were investigating the action of arachidonic acid on the function of ATP-sensitive K+(KA-re) channels that this study was started. KAX P channels play an important role in insulin secretion from pancreatic B-cells (Petersen and Dunne, 1989). The activity of this channel is reduced by nutri- ents such as glucose. This inhibition results in mem- brane depolarization, increased Ca 2÷ influx via volt- age-dependent Ca 2+ channels and, finally, increased Correspondence to: M. Lazdunski, Institut de Pharmacologie Mol~culaire et Cellulaire, CNRS, 660 Route des Lucioles, Sophia Antipolis 06560 Valbonne, France. Tel. 33.93 95 77 00, fax 33.93 95 7704. i Present address: Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland. insulin release. Antidiabetic sulfonylureas specifically bind to these channels and inhibit their activity (Schmid-Antomarchi et al., 1987). This channel is acti- vated by K + channel openers and particularly by diaz- oxide (Cook and Quast, 1989; Duty and Weston, 1990), a well-known inhibitor of insulin secretion. The present study shows that 8-MOP inhibits KAT p channels in HIT-T15 insulinoma cells and stimulates insulin release. 2. Materials and methods 2.1. Materials 8-Methoxypsoralen, oligomycin, trypsin, penicillin, streptomycin, polyornithine and ATP were from Sigma. Ham F12k medium was from Gibco; glibenclamide was from Hoechst. Diazoxide was from Cetrane. Horse and foetal calf sera were from Sebak. S6RbC1 was from Amersham. All other chemicals were of analytical grade. 2.2. Cell culture and 86Rb + efflux experiments HIT-T15 B-cells (ATCC, passage number 60) were cultured in Ham's F12k medium supplemented with 10% dialysed horse serum, 2.5% foetal calf serum, both inactivated, 25 mM bicarbonate, penicillin 100 U/ml, streptomycin 0.1 mg/ml at 37°C in humidified 5% CO2/95% air(Schmid-Antomarchi et al., 1987).