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- Title
Alternative splicing modulates the frequency-dependent response of CaMKII to Ca<sup>2+</sup> oscillations.
- Authors
Bayer, Kulrich; De Koninck, Paul; Schulman, Howard
- Abstract
Ca2+ oscillations are required in various signal transduction pathways, and contain information both in their amplitude and frequency. Remarkably, the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) can decode such frequencies. A Ca2+/CaM-stimulated autophosphorylation leads to Ca2+/CaM-independent (autonomous) activity of the kinase that outlasts the initial stimulation. This autonomous activity increases exponentially with the frequency of Ca2+ oscillations. Here we show that three β-CaMKII splice variants (βM, β and βe') have very similar specific activity and maximal autonomy. However, their autonomy generated by Ca2+ 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 β-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 Ca2+ oscillations.
- Subjects
OSCILLATIONS; GENETIC transduction; CELLULAR signal transduction; PROTEIN kinases; NERVOUS system; CELLS
- Publication
EMBO Journal, 2002, Vol 21, Issue 14, p3590
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/cdf360