title: Regulation of Ca2+/calmodulin-dependent protein kinase II by Ca2+/calmodulin-independent autophosphorylation.
abstract: The autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaM-KII) results in the generation of kinase activity that is largely Ca2+/CaM-independent. We report that continued Ca2+/CaM-independent autophosphorylation of CaM-KII results in the generation of distinct phosphopeptides as identified by high performance liquid chromatography and enzymatic properties that are different than those observed for Ca2+/CaM-dependent autophosphorylation. These Ca2+/CaM-independent properties include (a) increased catalytic activity, (b) higher substrate affinity for the phosphorylation of synapsin I, and (c) decreased CaM-binding to both CaM-KII subunits as analyzed by gel overlays. Our results indicate that the autophosphorylation of only one subunit per holoenzyme is required to generate the Ca2+/CaM-independent CaM-KII. We suggest a two-step process by which autophosphorylation regulates CaM-KII. Step I requires Ca2+/CaM and underlies initial kinase activation. Step II involves continued autophosphorylation of the Ca2+/CaM-independent kinase and results in increased affinity for its substrate synapsin I and decreased affinity for calmodulin. These results indicate a complex mechanism through which autophosphorylation of CaM-KII may regulate its activity in response to transient fluctuations in intracellular calcium.
authors.affiliation: Department of Neurobiology and Anatomy, University of Texas Health Science Center, Houston 77225.
authors.forename: R
authors.initials: R
authors.lastname: Lickteig
authors.forename: S
authors.initials: S
authors.lastname: Shenolikar
authors.forename: L
authors.initials: L
authors.lastname: Denner
authors.forename: P T
authors.initials: PT
authors.lastname: Kelly
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002147:Calmodulin / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004533:Egtazic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D013997:Time Factors
chemical_list: D002147:Calmodulin; D004533:Egtazic Acid; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases