Phase-locked signals elucidate circuit architecture of an oscillatory pathway.
| Autor: | Andreja Jovic, Bryan Howell, Michelle Cote, Susan M Wade, Khamir Mehta, Atsushi Miyawaki, Richard R Neubig, Jennifer J Linderman, Shuichi Takayama |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | PLoS Computational Biology, Vol 6, Iss 12, p e1001040 (2010) |
| Druh dokumentu: | article |
| ISSN: | 1553-734X 1553-7358 |
| DOI: | 10.1371/journal.pcbi.1001040 |
| Popis: | This paper introduces the concept of phase-locking analysis of oscillatory cellular signaling systems to elucidate biochemical circuit architecture. Phase-locking is a physical phenomenon that refers to a response mode in which system output is synchronized to a periodic stimulus; in some instances, the number of responses can be fewer than the number of inputs, indicative of skipped beats. While the observation of phase-locking alone is largely independent of detailed mechanism, we find that the properties of phase-locking are useful for discriminating circuit architectures because they reflect not only the activation but also the recovery characteristics of biochemical circuits. Here, this principle is demonstrated for analysis of a G-protein coupled receptor system, the M3 muscarinic receptor-calcium signaling pathway, using microfluidic-mediated periodic chemical stimulation of the M3 receptor with carbachol and real-time imaging of resulting calcium transients. Using this approach we uncovered the potential importance of basal IP3 production, a finding that has important implications on calcium response fidelity to periodic stimulation. Based upon our analysis, we also negated the notion that the Gq-PLC interaction is switch-like, which has a strong influence upon how extracellular signals are filtered and interpreted downstream. Phase-locking analysis is a new and useful tool for model revision and mechanism elucidation; the method complements conventional genetic and chemical tools for analysis of cellular signaling circuitry and should be broadly applicable to other oscillatory pathways. |
| Databáze: | Directory of Open Access Journals |
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