Intracellular diadenosine polyphosphates: a novel second messenger in stimulus‐secretion coupling

In pancreatic β‐cells, stimulatory glucose concentrations increase cytosolic diadenosine polyphosphates ([Ap n A] i ) to concentrations sufficient to block ATP‐sensitive K + (K ATP ) channels. High‐performance liquid chromatography and patch clamp techniques were used to study the metabolic pathways by which pancreatic β‐cells synthesize Ap n A and the mechanism through which Ap n A inhibit K ATP channels. Ap n A show a glucose‐ and time‐dependent cytosolic concentration increase parallel, though 30‐ to 50‐fold higher, to changes observed in adenine nucleotides. Other fuel secretagogues, leucine and 2‐ketoisocaproate, raise [Ap n A] i as efficiently as 22 mM glucose. Blockade of glycolysis or Krebs cycle decreases glucose‐induced [Ap n A] i . No significant increase in cytosolic Ap n A concentrations is induced by nonnutrient secretagogues or nonmetabolizable nutrient secretagogues. Inorganic pyrophosphatase inhibition with sodium fluoride blocks 22 mM glucose‐induced [Ap n A] i increase. Ap n A inhibition of K ATP channel resembles that of ATP in efficacy, but shows clear functional differences. Unlike ATP, Ap 4 A does not restore channel activity after rundown. Furthermore, these compounds do not compete with each other for the same site. These features suggest a prominent role for Ap 4 A in β‐cell function, comparable to ATP. We conclude that nutrient metabolism through pyrophosphatase activation is necessary to induce Ap n A synthesis, which in turn constitutes a new, ATP‐independent, metabolic regulator of K ATP channel activity.—Martı´n, F., Pintor, J., Rovira, J. M., Ripoll, C., Miras‐Portugal, M. T., Soria, B. Intracellular diadenosine polyphosphates: a novel second messenger in stimulus‐secretion coupling. FASEB J. 12, 1499–1506 (1998)