Diadenosine polyphosphates and the control of cyclic AMP concentrations in isolated rat liver cells

Abstract

Extracellular diadenosine polyphosphates (Ap n A), through their interactions with appropriate P 2 receptors, influence a diverse range of intracellular activities. In particular, Ap 4 A stimulates alterations in intracellular calcium homeostasis and subsequent activation of glycogen breakdown in isolated liver cells. Here we show that, like ATP, Ap 4 A and other naturally occurring diadenosine polyphosphates attenuate glucagon-stimulated accumulation of cyclic AMP in isolated rat liver cells. The characteristics of Ap 4 A-and ATP-dependent modulation of glucagon-stimulated cyclic AMP accumulation are similar. These results are discussed in the context of the repertoire of intracellular signalling processes modulated by extracellular nucleotides.z 1999 Federation of European Biochemical Societies.

Regulation of Rat Hepatocyte Function by P2Y Receptors: Focus on Control of Glycogen Phosphorylase and Cyclic AMP by 2-Methylthioadenosine 5′-Diphosphate

“…It is, however, consistent with a previous report by Edgecombe et al (1999) in which the inhibitory effects of ATP and Ap 4 A in freshly prepared rat hepatocytes were apparent only at concentrations greater than 100 M. We have demonstrated by HPLC that following a 3-min incubation of hepatocytes with 300 M 2-MeSADP only 56% was recovered. It may therefore be assumed that in the absence of any degradation the threshold concentration of 2-MeSADP for inhibition of glucagonstimulated cyclic AMP levels will be lower than that reported here.…”

“…Extracellular nucleotides play a well established role in the regulation of this key function in rat hepatocytes through the activation of P2Y receptors (Okajima et al, 1987;Keppens et al, 1992Keppens et al, , 1993Keppens, 1993), a family of G-protein-coupled receptors responding to the native nucleotides ADP, ATP, UDP, UTP, and UDP-glucose (Boarder and Hourani, 1998;Abbracchio et al, 2003). Curiously, stimulation of P2Y receptors on rat hepatocytes leads to both increases in [Ca 2ϩ ] c and inhibition of adenylyl cyclase; these responses will stimulate and limit, respectively, activation of glycogen phosphorylase (Okajima et al, 1987;Dixon et al, 1990Dixon et al, , 1995Dixon et al, , 2000Keppens et al, 1992;1993;Keppens, 1993;Edgecombe et al, 1999). The mechanism underlying the regulation of glycogen phosphorylase by cyclic AMP is well established, with increased cyclic AMP levels leading to phosphorylation and activation of the enzyme, and with dephosphorylation by protein phosphatase 1 as cyclic AMP levels fall.…”