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Epinephrine-induced hyperpolarization of islet cells without K_ATP channels

¹Institut für Neurophysiologie, Universität zu Köln, 50931 Cologne, Germany; and ²Department of Molecular and Cellular Biology and ³Department of Medicine/Endocrinology, Baylor College of Medicine, Houston, Texas 77030

Submitted 14 August 2003 ; accepted in final form 28 October 2003

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⁺ (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 -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 -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 ₂-adrenoceptor agonist and inhibited by -yohimbine, an ₂-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 µM) in the patch pipette did not significantly alter these currents or activate novel inward-rectifying K⁺ currents. We conclude that epinephrine can hyperpolarize -cells in the absence of K_ATP channels via activation of low-conductance BaCl₂-sensitive K⁺ channels that are regulated by pertussis toxin-sensitive G proteins.

insulin secretion; ABCC8; sulfonylurea receptor-1 knockout mice; pertussis toxin; membrane potential; adenosine triphosphate-sensitive potassium channels

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