Lobe-specific Functions of Ca2+•Calmodulin in αCa2+•Calmodulin-dependent Protein Kinase II Activation

N-Methyl-D-aspartic acid receptor-dependent long term potentiation (LTP), a model of memory formation, requires Ca2+center dot calmodulin-dependent protein kinase II (alpha CaMKII) activity and Thr(286) autophosphorylation via both global and local Ca2+ signaling, but the mechanisms of signal transduction are not understood. We tested the hypothesis that the Ca2+-binding activator protein calmodulin (CaM) is the primary decoder of Ca2+ signals, thereby determining the output, e. g. LTP. Thus, we investigated the function of CaM mutants, deficient in Ca2+ 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 alpha CaMKII. Occupancy of CaM Ca2+ binding sites 1, 3, and 4 is necessary and sufficient for full activation. Moreover, the N- and C-terminal CaM lobes have distinct functions. Ca2+ binding toNlobe Ca2+ binding site 1 increases the turnover rate of the enzyme 5-fold, whereas the Clobe plays a dual role; it is required for full activity, but in addition, via Ca2+ binding site 3, it stabilizes ATP binding to alpha CaMKII 4-fold. Thr(286) autophosphorylation is also dependent on Ca2+ 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) Ca2+ signals, but occupancy of N lobe site 1 and thus activation of alpha CaMKII requires high amplitude/high frequency (local) Ca2+ signals, lobe-specific sensing of Ca2+ signaling patterns by CaM is proposed to explain the requirement for both global and local Ca2+ signaling in the induction of LTP via alpha CaMKII.