DIADENOSINE POLYPHOSPHATE-STIMULATED GLUCONEOGENESIS IN ISOLATED RAT PROXIMAL TUBULES

Diadenosine polyphosphates released into the extracellular environment influence a variety of metabolic and other cellular activities in a w ide range of target tissues. Here we have studied the impact of these novel nucleotides on gluconeogenesis in isolated rat proximal tubules. Gluconeogenesis was stimulated following exposure of isolated proxima l tubules to a range of adenine-containing nucleotides including ADP, ATP, Ap(3)A, Ap(4)A, Ap(5)A and Ap(6)A. The concentration-dependence o f ATP-, Ap(3)A- and Ap(4)A-mediated stimulation of gluconeogenesis was similar and was consistent with a role for these agents in the physio logical control of renal metabolism. Nucleotide-stimulated gluconeogen esis was diminished in the presence of agents that interfere with phos pholipase C activation or intracellular Ca2+ metabolism, indicative of a role for polyphosphoinositide-mediated Ca2+ mobilization in the mec hanism of action of ATP, Ap(3)A and Ap(4)A. The characteristics of bin ding of [2-H-3]Ap(4)A to renal plasma-membrane preparations suggest th at Ap(4)A mediates its effects on proximal tubule gluconeogenesis via interaction with P-2y-like purinoceptor(s) also recognized by extracel lular ATP.