Neuronal Ca²⁺/Calmodulin-Dependent Protein Kinase II: The Role of Structure and Autoregulation in Cellular Function

Abstract

Highly enriched in brain tissue and present throughout the body, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is central to the coordination and execution of Ca(2+) signal transduction. The substrates phosphorylated by CaMKII are implicated in homeostatic regulation of the cell, as well as in activity-dependent changes in neuronal function that appear to underlie complex cognitive and behavioral responses, including learning and memory. The architecture of CaMKII holoenzymes is unique in nature. The kinase functional domains (12 per holoenzyme) are attached by stalklike appendages to a gear-shaped core, grouped into two clusters of six. Each subunit contains a catalytic, an autoregulatory, and an association domain. Ca(2+)/calmodulin (CaM) binding disinhibits the autoregulatory domain, allowing autophosphorylation and complex changes in the enzyme's sensitivity to Ca(2+)/CaM, including the generation of Ca(2+)/CaM-independent activity, CaM trapping, and CaM capping. These processes confer a type of molecular memory to the autoregulation and activity of CaMKII. Its function is intimately shaped by its multimeric structure, autoregulation, isozymic type, and subcellular localization; these features and processes are discussed as they relate to known and potential cellular functions of this multifunctional protein kinase.

αCaMKII autophosphorylation levels differ depending on subcellular localization

“…CaMKII is activated when increases in intracellular Ca 2+ concentration lead to the binding of Ca 2+ /calmodulin complexes to the kinase, relieving auto-inhibition (Hudmon and Schulman, 2002). If the Ca 2+ signal is strong enough, and two adjacent subunits in the CaMKII holoenzyme are activated, then an intersubunit autophosphorylation can occur on threonine 286 (T286) of the α subunit (threonine 287 of the β, γ, and δ subunits) (Hanson et al, 1994;Rich and Schulman, 1998;Mukherji and Soderling, 1994;Miller et al, 1988).…”

Chronic Antidepressants Induce Redistribution and Differential Activation of αCaM Kinase II between Presynaptic Compartments

“…We found that drugs with different primary mechanisms (serotonin and/or norepinephrine reuptake inhibition) upregulated CaM kinase II enzymatic activity in total extracts from HC and P/FC; the increase was more remarkable for Ca 2 + -independent activity in HC (see Figure 2a and b). In this area, the kinase activation was accompanied by a slight but not significant increase of autophosphorylation at Thr 286 (for FLX and RBX), which represents the canonical mechanism for activity-induced activation of this kinase (Hudmon and Schulman, 2002;Lisman et al, 2002). We reported previously upregulation of CaM kinase II activity by pronoradrenergic antidepressants in cell bodies of pyramidal and granular neurons of HC (Tiraboschi et al, 2004a); our previous and present results strongly suggest that the modifications observed in total HC extract are mainly related to cell bodies and that this mechanism seems to be common to pronoadrenergic (DMI and RBX) and proserotonergic (FLX) antidepressants.…”

“…CaM kinase II is an abundant protein kinase in brain, regulating neuronal response to calcium fluxes with a pivotal role in neuroplasticity (Hudmon and Schulman, 2002;Lisman et al, 2002). The kinase is activated by the binding of Ca 2 + /CaM that generates Ca 2 + -dependent enzymatic activity.…”

Modulation of αCaMKII signaling by rapid ERα action

“…This permits the activation of one subunit while the second subunit undergoes a conformational change, revealing Thr286 to the active subunit for phosphorylation. CaMKII remains actives until it is dephosphorylated, even when Ca 2+ levels return to normal (Hanson, 1992;Hudmon, 2002).…”