Methylglyoxal causes swelling and activation of a volume-sensitive anion conductance in rat pancreatic beta-cells.
Membrane potential and whole-cell current were studied in rat pancreatic beta-cells using the 'perforated patch' technique and cell volume measured by a video-imaging method. Exposure of beta-cells to the alpha-ketoaldehyde methylglyoxal (1 mM) resulted in depolarization and electrical activity. In cells voltage-clamped at -70 mV, this effect was accompanied by the development of inward current noise. In voltage-pulse experiments, methylglyoxal activated an outwardly rectifying conductance which was virtually identical to the volume-sensitive anion conductance previously described in these cells. Two inhibitors of this conductance, 4,4'-dithiocyanatostilbene-2,2'-disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), also inhibited the depolarization and inward current evoked by methylglyoxal. Methylglyoxal increased beta-cell volume to a relative value of 1.33 after 10 min with a gradual return towards basal levels following withdrawal of the alpha-ketoaldehyde. None of the effects of methylglyoxal was observed in response to t-butylglyoxal which, unlike methylglyoxal, is a poor substrate for the glyoxalase pathway. Methylglyoxal had no apparent effect on beta-cell K+ channel activity. It is suggested that the metabolism of methylglyoxal to D-lactate causes beta-cell swelling and activation of the volume-sensitive anion channel, leading to depolarization. These findings could be relevant to the stimulatory action of D-glucose, the metabolism of which generates significant quantities of L-lactate.
Best
L
L
Department of Medicine, University of Manchester, Oxford Road, Manchester, M13 9WL, UK.
Miley
H E
HE
Brown
P D
PD
Cook
L J
LJ
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D000838:Anions; D005260:Female; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009579:Nitrobenzoates / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012414:Rubidium Radioisotopes
D000838:Anions; D007473:Ion Channels; D009579:Nitrobenzoates; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D011765:Pyruvaldehyde; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid