Alternative splicing modulates the frequency-dependent response of CaMKII to Ca(2+) oscillations.

TitleAlternative splicing modulates the frequency-dependent response of CaMKII to Ca(2+) oscillations.
Publication TypeJournal Article
Year of Publication2002
AuthorsBayer K U, De Koninck P, Schulman H
JournalEMBO J
Volume21
Issue14
Pagination3590-7
Date Published2002 Jul 15
ISSN0261-4189
KeywordsAlternative Splicing, Amino Acid Sequence, Animals, Base Sequence, Brain, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Cloning, Molecular, COS Cells, Molecular Sequence Data, Phosphorylation
Abstract

Ca(2+) oscillations are required in various signal trans duction pathways, and contain information both in their amplitude and frequency. Remarkably, the Ca(2+)/calmodulin(CaM)-dependent protein kinase II (CaMKII) can decode such frequencies. A Ca(2+)/CaM-stimulated autophosphorylation leads to Ca(2+)/CaM-independent (autonomous) activity of the kinase that outlasts the initial stimulation. This autonomous activity increases exponentially with the frequency of Ca(2+) oscillations. Here we show that three beta-CaMKII splice variants (beta(M), beta and beta(e)') have very similar specific activity and maximal autonomy. However, their autonomy generated by Ca(2+) oscillations differs significantly. A mechanistic basis was found in alterations of the CaM activation constant and of the initial rate of autophosphorylation. Structurally, the splice variants differ only in a variable 'linker' region between the kinase and association domains. Therefore, we propose that differences in relative positioning of kinase domains within multimeric holoenzymes are responsible for the observed effects. Notably, the beta-CaMKII splice variants are differentially expressed, even among individual hippocampal neurons. Taken together, our results suggest that alternative splicing provides cells with a mechanism to modulate their sensitivity to Ca(2+) oscillations.

DOI10.1093/emboj/cdf360
Alternate JournalEMBO J.
PubMed ID12110572
PubMed Central IDPMC126106

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