This study examines the effect of epinephrine, a known physiologic inhibitor of insulin secretion, on the membrane potential of pancreatic islet cells from Sur1 (ABCC8) null mice, Sur1KO, which lack functional 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 rauwolscine, an ₂-antagonist. A selection of K⁺ channel inhibitors, TEA, apamin, dendrotoxin, iberiotoxin, E4130, chromanol 293B, and terziapin 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 mV and 0 mV, respectively. GTPS (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.