Dual effect of NO on K(+)(ATP) current of mouse pancreatic B-cells: stimulation by deenergizing mitochondria and inhibition by direct interaction with the channel.
Nitric oxide (NO) is assumed to contribute to the impairment of B-cell function in type 1 diabetes mellitus (IDDM). In the present paper we show that in mouse B-cells with intact metabolism authentic NO (20 microM) led to a biphasic effect on the K(+)(ATP) current, namely a transient increase and a consecutive almost complete inhibition. This resembles closely the effect that we have observed previously with the NO donor S-nitrosocysteine (SNOC, 1 mM) suggesting that merely NO caused both phases of this effect. We now demonstrate that the rise in the current amplitude was accompanied by a depolarization of the mitochondrial membrane potential DeltaPsi and a concomitant reduction in the ATP/ADP ratio. Thus, it seems likely that the increase in current amplitude is due to the interference of NO with cell metabolism. The subsequent inhibition of the K(+)(ATP) current is assumed to be caused by a direct effect on the channel since K(+)(ATP) single channel current activity measured in excised patches was strongly reduced by authentic NO and SNOC. Our data reveal new insights into the mechanisms underlying the biphasic action of NO on K(+)(ATP) channels in pancreatic B-cells.
Drews
G
G
Institute of Pharmacy, Department of Pharmacology, Auf der Morgenstelle 8, University of Tübingen, D-72076, Tübingen, Germany. gisela.drews@uni-tuebingen.de
Krämer
C
C
Krippeit-Drews
P
P
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D026403:S-Nitrosothiols
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D015221:Potassium Channels; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C021315:S-nitrosocysteine; D003545:Cysteine