Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations: a simple model.

TitleSensitivity of CaM kinase II to the frequency of Ca2+ oscillations: a simple model.
Publication TypeJournal Article
Year of Publication2003
AuthorsDupont G, Houart G, De Koninck P
JournalCell Calcium
Volume34
Issue6
Pagination485-97
Date Published2003 Dec
ISSN0143-4160
KeywordsBiophysical Phenomena, Biophysics, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Calmodulin, Computer Simulation, Enzyme Activation, Enzymes, Immobilized, Kinetics, Models, Biological, Models, Molecular, Phosphorylation, Protein Subunits, Sensitivity and Specificity, Signal Transduction
Abstract

The rules that govern the activation and autophosphorylation of the multifunctional Ca2+-calmodulin kinase II (CaMKII) by Ca2+ and calmodulin (CaM) are thought to underlie its ability to decode Ca2+ oscillations and to control multiple cellular functions. We propose a simple biophysical model for the activation of CaMKII by Ca2+ and calmodulin. The model describes the transition of the subunits of the kinase between their different possible states (inactive, bound to Ca2+-CaM, phosphorylated at Thr(286), trapped and autonomous). All transitions are described by classical kinetic equations except for the autophosphorylation step, which is modeled in an empirical manner. The model quantitatively reproduces the experimentally demonstrated frequency sensitivity of CaMKII [Science 279 (1998) 227]. We further use the model to investigate the role of several characterized features of the kinase--as well as some that are not easily attainable by experiments--in its frequency-dependent responses. In cellular microdomains, CaMKII is expected to sense very brief Ca2+ spikes; our simulations under such conditions reveal that the enzyme response is tuned to optimal frequencies. This prediction is then confirmed by experimental data. This novel and simple model should help in understanding the rules that govern CaMKII regulation, as well as those involved in decoding intracellular Ca2+ signals.

Alternate JournalCell Calcium
PubMed ID14572807

Funding

Our research endeavors are made possible by the following agencies:

Canadian Institutes of Health Research - Instituts de recherche en santé du Canada Fonds de recherche du Québec – Nature et technologies (FRQNT)Fonds de la recherche en santé du Québec NARSAD Natural Sciences and Engineering Research Council of Canada (NSERC) - Conseil de recherche en sciences naturelles et en génie du Canada (CRSNG)innovation.caHuman Frontier Science Program