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 (SurIKO), which lack functional ATP-sensitive K+ (K-ATP) 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 Ca2+-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 alpha(2)-adrenoceptor agonist and inhibited by alpha-vohimbine, an alpha(2)-antagonist. A selection of K+ channel inhibitors, tetraethylammonium, apamin, dendrotoxin, iberiotoxin. E-4130, chromanol 29313, 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 muM) 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.