Lobe-specific Functions of Ca(2+)·Calmodulin in αCa(2+)·Calmodulin-dependent Protein Kinase II Activation

N-Methyl-d-aspartic acid receptor-dependent long term potentiation (LTP), a model of memory formation, requires Ca(2+)·calmodulin-dependent protein kinase II (αCaMKII) activity and Thr(286) autophosphorylation via both global and local Ca(2+) signaling, but the mechanisms of signal transduction are not understood. We tested the hypothesis that the Ca(2+)-binding activator protein calmodulin (CaM) is the primary decoder of Ca(2+) signals, thereby determining the output, e.g. LTP. Thus, we investigated the function of CaM mutants, deficient in Ca(2+) binding at sites 1 and 2 of the N-terminal lobe or sites 3 and 4 of the C-terminal CaM lobe, in the activation of αCaMKII. Occupancy of CaM Ca(2+) binding sites 1, 3, and 4 is necessary and sufficient for full activation. Moreover, the N- and C-terminal CaM lobes have distinct functions. Ca(2+) binding to N lobe Ca(2+) binding site 1 increases the turnover rate of the enzyme 5-fold, whereas the C lobe plays a dual role; it is required for full activity, but in addition, via Ca(2+) binding site 3, it stabilizes ATP binding to αCaMKII 4-fold. Thr(286) autophosphorylation is also dependent on Ca(2+) binding sites on both the N and the C lobes of CaM. As the CaM C lobe sites are populated by low amplitude/low frequency (global) Ca(2+) signals, but occupancy of N lobe site 1 and thus activation of αCaMKII requires high amplitude/high frequency (local) Ca(2+) signals, lobe-specific sensing of Ca(2+)-signaling patterns by CaM is proposed to explain the requirement for both global and local Ca(2+) signaling in the induction of LTP via αCaMKII.