title: Reliable encoding of stimulus intensities within random sequences of intracellular Ca2+ spikes.
abstract: Ca(2+) is a ubiquitous intracellular messenger that regulates diverse cellular activities. Extracellular stimuli often evoke sequences of intracellular Ca(2+) spikes, and spike frequency may encode stimulus intensity. However, the timing of spikes within a cell is random because each interspike interval has a large stochastic component. In human embryonic kidney (HEK) 293 cells and rat primary hepatocytes, we found that the average interspike interval also varied between individual cells. To evaluate how individual cells reliably encoded stimuli when Ca(2+) spikes exhibited such unpredictability, we combined Ca(2+) imaging of single cells with mathematical analyses of the Ca(2+) spikes evoked by receptors that stimulate formation of inositol 1,4,5-trisphosphate (IP3). This analysis revealed that signal-to-noise ratios were improved by slow recovery from feedback inhibition of Ca(2+) spiking operating at the whole-cell level and that they were robust against perturbations of the signaling pathway. Despite variability in the frequency of Ca(2+) spikes between cells, steps in stimulus intensity caused the stochastic period of the interspike interval to change by the same factor in all cells. These fold changes reliably encoded changes in stimulus intensity, and they resulted in an exponential dependence of average interspike interval on stimulation strength. We conclude that Ca(2+) spikes enable reliable signaling in a cell population despite randomness and cell-to-cell variability, because global feedback reduces noise, and changes in stimulus intensity are represented by fold changes in the stochastic period of the interspike interval.
authors: Mathematical Cell Physiology, Max Delbrück Center for Molecular Medicine, Robert Rössle Straße 10, Berlin 13125, Germany. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. Institute for Theoretical Biology, Charité-Universitätsmedizin Berlin, Invalidenstraße 43, Berlin 10115, Germany.
authors: Kevin
authors: K
authors: Thurley
authors: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors: Stephen C
authors: SC
authors: Tovey
authors: Mathematical Cell Physiology, Max Delbrück Center for Molecular Medicine, Robert Rössle Straße 10, Berlin 13125, Germany.
authors: Gregor
authors: G
authors: Moenke
authors: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
authors: Victoria L
authors: VL
authors: Prince
authors: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors: Abha
authors: A
authors: Meena
authors: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
authors: Andrew P
authors: AP
authors: Thomas
authors: Luxembourg Centre for Systems Biomedicine, 7 Avenue des Hauts Fourneaux, Esch sur Alzette 4362, Luxembourg. National Center for Microscopy and Imaging Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Alexander
authors: A
authors: Skupin
authors: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. martin.falcke@mdc-berlin.de cwt1000@cam.ac.uk.
authors: Colin W
authors: CW
authors: Taylor
authors: Mathematical Cell Physiology, Max Delbrück Center for Molecular Medicine, Robert Rössle Straße 10, Berlin 13125, Germany. Department of Physics, Humboldt University Berlin, Newtonstraße 15, Berlin 12489, Germany. martin.falcke@mdc-berlin.de cwt1000@cam.ac.uk.
authors: Martin
authors: M
authors: Falcke
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008954:Models, Biological; D010656:Phenylephrine / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015203:Reproducibility of Results; D059010:Single-Cell Analysis / Q000379:methods; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D018679:Cholinergic Agonists; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D010656:Phenylephrine; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D002118:Calcium