Epinephrine-induced hyperpolarization of islet cells without KATP channels.
This study examines the effect of epinephrine, a known physiological inhibitor of insulin secretion, on the membrane potential of pancreatic islet cells from sulfonylurea receptor-1 (ABCC8)-null mice (Sur1KO), which lack functional ATP-sensitive K+ (KATP) channels. These channels have been argued to be activated by catecholamines, but epinephrine effectively inhibits insulin secretion in both Sur1KO and wild-type islets and in mice. Isolated Sur1KO beta-cells are depolarized in both low (2.8 mmol/l) and high (16.7 mmol/l) glucose and exhibit Ca(2+)-dependent action potentials. Epinephrine hyperpolarizes Sur1KO beta-cells, inhibiting their spontaneous action potentials. This effect, observed in standard whole cell patches, is abolished by pertussis toxin and blocked by BaCl2. The epinephrine effect is mimicked by clonidine, a selective alpha2-adrenoceptor agonist and inhibited by alpha-yohimbine, an alpha2-antagonist. A selection of K+ channel inhibitors, tetraethylammonium, apamin, dendrotoxin, iberiotoxin, E-4130, chromanol 293B, and tertiapin did not block the epinephrine-induced hyperpolarization. Analysis of whole cell currents revealed an inward conductance of 0.11 +/- 0.04 nS/pF (n = 7) and a TEA-sensitive outward conductance of 0.55 +/- 0.08 nS/pF (n = 7) at -60 and 0 mV, respectively. Guanosine 5'-O-(3-thiotriphosphate) (100 microM) in the patch pipette did not significantly alter these currents or activate novel inward-rectifying K+ currents. We conclude that epinephrine can hyperpolarize beta-cells in the absence of KATP channels via activation of low-conductance BaCl2-sensitive K+ channels that are regulated by pertussis toxin-sensitive G proteins.
Sieg
Andrea
A
Institut für Neurophysiologie, Universität zu Köln, Cologne, Germany.
Su
Jiping
J
Muñoz
Alvaro
A
Buchenau
Michael
M
Nakazaki
Mitsuhiro
M
Aguilar-Bryan
Lydia
L
Bryan
Joseph
J
Ullrich
Susanne
S
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004837:Epinephrine / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency*; D009543:Nifedipine / Q000494:pharmacology; D015221:Potassium Channels / Q000145:classification / Q000172:deficiency / Q000187:drug effects* / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D004837:Epinephrine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009543:Nifedipine; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C577508:Abcc8 protein, mouse