Elevated intracellular cyclic AMP exerts different modulatory effects on cytosolic free Ca2+ oscillations induced by ADP and ATP in single rat hepatocytes

Abstract

Single aequorin-injected hepatocytes respond to agonists acting via the phosphoinositide signalling pathway by the generation of oscillations in cytosolic free Ca2+ concentration ([Ca2+]free). The duration of [Ca2+]free transients is characteristic of the stimulating agonist. We have previously reported that ADP and ATP, which are believed to act through a single P(2y)-purinoceptor species, induce very different oscillatory [Ca2+]free responses in the majority of hepatocytes. We have interpreted these data as evidence for two separate Ca(2+)-mobilizing purinoceptors for these nucleotides. We show here that the elevation of intracellular cyclic AMP concentration, by the co-application of either dibutyryl cyclic AMP or 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino)butyryl]- forskolin (L858051), exerts different modulatory effects on [Ca2+]free oscillations induced by ADP and ATP in single rat hepatocytes. Elevated intracellular cyclic AMP levels enhance the frequency and peak [Ca2+]free of transients induced by ADP. In contrast, the elevation of intracellular cyclic AMP levels in hepatocytes producing [Ca2+]free oscillations in response to ATP stimulates either an increase in the duration of transients or a sustained rise in [Ca2+]free. The data illustrate a further difference between the oscillatory [Ca2+]free responses of hepatocytes to ADP and ATP, thus further arguing against ADP and ATP acting via a single purinoceptor species.

Actions of ADP, but not ATP, on cytosolic free Ca2+ in single rat hepatocytes mimicked by 2‐methylthioATP

“…A second group produce transients of much longer duration (up to 2 min), whereas in the final group, ATP induces transients of variable duration within a single response (Dixon et al, 1990). We have previously reported additional agonist-specific differences between ADP and ATh, in the effects of high agonist concentrations (Cobbold et al, 1988), and in the modulatory effects of elevated adenosine 3'5'-cyclic monophosphate (cyclic AMP) levels (Green et al, 1994) and coaddition of a,f,-MeATP (Dixon et al, 1993). We have argued that these differences in the oscillatory responses of single hepatocytes to ADP and ATP are inconsistent with their effects being mediated by a single receptor (Dixon et al, 1990;Green et al, 1994).…”

“…We have argued that these differences in the oscillatory responses of single hepatocytes to ADP and ATP are inconsistent with their effects being mediated by a single receptor (Dixon et al, 1990;Green et al, 1994). Indeed, we have proposed that the receptor mediating the response to ADP is distinct from the receptor(s) mediating the effects of ATP (Green et al, 1994 PhamacolM (1995) 116,[1979][1980][1981][1982][1983][1984] 1C. Dixon et al Ca2 responses of hepatocytes to 2-metylthloATP differences we have previously reported in the [Ca2+]i responses of hepatocytes to ADP and ATP, we demonstrate that, rather than acting as an analogue of ATP, 2-meSATP in fact mimics precisely the actions of ADP.…”

“…We have previously reported additional agonist-specific differences between ADP and ATh, in the effects of high agonist concentrations (Cobbold et al, 1988), and in the modulatory effects of elevated adenosine 3'5'-cyclic monophosphate (cyclic AMP) levels (Green et al, 1994) and coaddition of a,f,-MeATP (Dixon et al, 1993). We have argued that these differences in the oscillatory responses of single hepatocytes to ADP and ATP are inconsistent with their effects being mediated by a single receptor (Dixon et al, 1990;Green et al, 1994). Indeed, we have proposed that the receptor mediating the response to ADP is distinct from the receptor(s) mediating the effects of ATP (Green et al, 1994 PhamacolM (1995) 116,[1979][1980][1981][1982][1983][1984] 1C.…”

Different types of bursting calcium oscillations in non-excitable cells

“…The biological importance of bursting oscillations is well established. Bursting behaviour was found to be the primary mode of information processing and signal transduction in many biological systems, like for example in different neuron types, pancreatic b-cells and hepatocytes [1][2][3][4][5][6][7][8][9][24][25][26][27]. It has been shown that biologically relevant information of Ca 2þ oscillations is primarily frequency encoded [46,[53][54][55][56][57][58].…”

“…[23]) as well as in nonexcitable cells [24][25][26][27]. Trying to explain the mechanism of bursting Ca 2þ oscillations, several mathematical models for complex Ca 2þ oscillations in excitable [23] as well as in non-excitable cells [28][29][30][31] were proposed.…”