Format

Send to

Choose Destination
See comment in PubMed Commons below
Sci Signal. 2013 Jul 9;6(283):ra56. doi: 10.1126/scisignal.2003649.

Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA.

Author information

1
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA. sbandara@alumni.stanford.edu

Abstract

Assigning molecular functions and revealing dynamic connections between large numbers of partially characterized proteins in regulatory networks are challenges in systems biology. We showed that functions of signaling proteins can be discovered with a differential equations model of the underlying signaling process to extract specific molecular parameter values from single-cell, time-course measurements. By analyzing the effects of 250 small interfering RNAs on Ca(2+) signals in single cells over time, we identified parameters that were specifically altered in the Ca(2+) regulatory system. Analysis of the screen confirmed known functions of the Ca(2+) sensors STIM1 (stromal interaction molecule 1) and calmodulin and of Ca(2+) channels and pumps localized in the endoplasmic reticulum (ER) or plasma membrane. Furthermore, we showed that the Alzheimer's disease-linked protein presenilin-2 and the channel protein ORAI2 prevented overload of ER Ca(2+) and that feedback from Ca(2+) to phosphatidylinositol 4-kinase and PLCδ (phospholipase Cδ) may regulate the abundance of the plasma membrane lipid PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to control Ca(2+) extrusion. Thus, functions of signaling proteins and dynamic regulatory connections can be identified by extracting molecular parameter values from single-cell, time-course data.

PMID:
23838183
PMCID:
PMC3897207
DOI:
10.1126/scisignal.2003649
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center