Generation of calcium oscillations in fibroblasts by positive feedback between calcium and IP3.

A wide variety of nonexcitable cells generate repetitive transient increases in cytosolic calcium ion concentration ([Ca2+]i) when stimulated with agonists that engage the phosphoinositide signalling pathway. Current theories regarding the mechanisms of oscillation disagree on whether Ca2+ inhibits or stimulates its own release from internal stores and whether inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG) also undergo oscillations linked to the Ca2+ spikes. In this study, Ca2+ was found to stimulate its own release in REF52 fibroblasts primed by mitogens plus depolarization. However, unlike Ca2+ release in muscle and nerve cells, this amplification was insensitive to caffeine or ryanodine and required hormone receptor occupancy and functional IP3 receptors. Oscillations in [Ca2+]i were accompanied by oscillations in IP3 concentration but did not require functional protein kinase C. Therefore, the dominant feedback mechanism in this cell type appears to be Ca2+ stimulation of phospholipase C once this enzyme has been activated by hormone receptors.

[1]  Michael J. Berridge,et al.  Inositol phosphates and cell signalling , 1989, Nature.

[2]  P. Palade,et al.  Pharmacologic differentiation between inositol-1,4,5-trisphosphate-induced Ca2+ release and Ca2+- or caffeine-induced Ca2+ release from intracellular membrane systems. , 1989, Molecular pharmacology.

[3]  R Jacob,et al.  Calcium oscillations in electrically non-excitable cells. , 1990, Biochimica et biophysica acta.

[4]  L. Stryer,et al.  Molecular model for receptor-stimulated calcium spiking. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Y. Nozawa,et al.  Defective formation of inositol 1,4,5-trisphosphate in bradykinin-stimulated fibroblasts from progressive systemic sclerotic patients. , 1988, Biochemical and biophysical research communications.

[6]  J. Meldolesi,et al.  Spontaneous [Ca2+]i fluctuations in rat chromaffin cells do not require inositol 1,4,5-trisphosphate elevations but are generated by a caffeine- and ryanodine-sensitive intracellular Ca2+ store. , 1990, The Journal of biological chemistry.

[7]  R Y Tsien,et al.  Photochemically generated cytosolic calcium pulses and their detection by fluo-3. , 1989, The Journal of biological chemistry.

[8]  I. Parker,et al.  Inhibition by Ca2+ of inositol trisphosphate-mediated Ca2+ liberation: a possible mechanism for oscillatory release of Ca2+. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Brown,et al.  Receptor-mediated inositol phosphate formation in relation to calcium mobilization: a comparison of two cell lines. , 1987, Molecular pharmacology.

[10]  M. Berridge,et al.  Spatial and temporal aspects of cell signalling. , 1988, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[11]  U. Ruegg,et al.  Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases , 1989 .

[12]  N. Dean,et al.  Methods for the analysis of inositol phosphates. , 1989, Analytical biochemistry.

[13]  M. Endo,et al.  Calcium Induced Release of Calcium from the Sarcoplasmic Reticulum of Skinned Skeletal Muscle Fibres , 1970, Nature.

[14]  E J Sass,et al.  Characterization of cytosolic calcium oscillations induced by phenylephrine and vasopressin in single fura-2-loaded hepatocytes. , 1989, The Journal of biological chemistry.

[15]  A Goldbeter,et al.  Minimal model for signal-induced Ca2+ oscillations and for their frequency encoding through protein phosphorylation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Rozengurt,et al.  Disappearance of Ca2+-sensitive, phospholipid-dependent protein kinase activity in phorbol ester-treated 3T3 cells. , 1984, Biochemical and biophysical research communications.

[17]  David A. Eberhard,et al.  Intracellular Ca2+ activates phospholipase C , 1988, Trends in Neurosciences.

[18]  J. Kaplan,et al.  Photochemical manipulation of divalent cation levels. , 1990, Annual review of physiology.

[19]  D. Koshland,et al.  Domain structure and phosphorylation of protein kinase C. , 1987, The Journal of biological chemistry.

[20]  R. Tsien,et al.  Biologically useful chelators that release Ca2+ upon illumination , 1988 .

[21]  Eugene M. Johnson,et al.  Retrograde transport of nerve growth factor (NGF) in motoneurons of developing rats: Assessment of potential neurotrophic effects , 1988, Neuron.

[22]  Y. Hannun,et al.  Functions of sphingolipids and sphingolipid breakdown products in cellular regulation. , 1989, Science.

[23]  P. Cobbold,et al.  Agonist-induced oscillations in cytoplasmic free calcium concentration in single rat hepatocytes. , 1987, Cell calcium.

[24]  S. Y. Lee,et al.  Studies of inositol phospholipid-specific phospholipase C. , 1989, Science.

[25]  J. Mullaney,et al.  Competitive, reversible, and potent antagonism of inositol 1,4,5-trisphosphate-activated calcium release by heparin. , 1988, Journal of Biological Chemistry.

[26]  H. Motulsky,et al.  Alpha 2-adrenergic receptor stimulation mobilizes intracellular Ca2+ in human erythroleukemia cells. , 1989, The Journal of biological chemistry.

[27]  Ole H. Petersen,et al.  Pulsatile intracellular calcium release does not depend on fluctuations in inositol trisphosphate concentration , 1989, Nature.

[28]  Toshio Kitazawa,et al.  Cytosolic heparin inhibits muscarinic and alpha-adrenergic Ca2+ release in smooth muscle. Physiological role of inositol 1,4,5-trisphosphate in pharmacomechanical coupling. , 1989, The Journal of biological chemistry.

[29]  R. Payne,et al.  Feedback inhibition by calcium limits the release of calcium by inositol trisphosphate in Limulus ventral photoreceptors , 1990, Neuron.