Alternative splicing modulates the frequency-dependent response of CaMKII to Ca2+ oscillations

Ca2+ oscillations are required in various signal trans duction 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 beta-CaMKII splice variants (beta(M), beta and beta(e)') 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 beta-CaMKII splice variants are differ entially 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.