title: Lobe-specific functions of Ca2+·calmodulin in alphaCa2+·calmodulin-dependent protein kinase II activation.
abstract: N-methyl-D-aspartic acid receptor-dependent long term potentiation (LTP), a model of memory formation, requires Ca2+·calmodulin-dependent protein kinase II (αCaMKII) activity and Thr286 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 αCaMKII. 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 to N lobe Ca2+ 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 Ca2+ binding site 3, it stabilizes ATP binding to αCaMKII 4-fold. Thr286 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 αCaMKII 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 αCaMKII.
authors.affiliation: Division of Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Abdirahman M
authors.initials: AM
authors.lastname: Jama
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gabriel
authors.forename: Ahmed J
authors.initials: AJ
authors.lastname: Al-Nagar
authors.forename: Stephen
authors.initials: S
authors.lastname: Martin
authors.forename: Sana Z
authors.initials: SZ
authors.lastname: Baig
authors.forename: Homan
authors.initials: H
authors.lastname: Soleymani
authors.forename: Zawahir
authors.initials: Z
authors.lastname: Chowdhury
authors.forename: Philip
authors.initials: P
authors.lastname: Beesley
authors.forename: Katalin
authors.initials: K
authors.lastname: Török
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D010766:Phosphorylation; D018411:Spodoptera
chemical_list: D002147:Calmodulin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium