CaMKII in cerebral ischemia

Abstract

Ischemic insults on neurons trigger excessive, pathological glutamate release that causes Ca²⁺ overload resulting in neuronal cell death (excitotoxicity). The Ca²⁺/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of physiological excitatory glutamate signals underlying neuronal plasticity and learning. Glutamate stimuli trigger autophosphorylation of CaMKII at T286, a process that makes the kinase "autonomous" (partially active independent from Ca²⁺ stimulation) and that is required for forms of synaptic plasticity. Recent studies suggested autonomous CaMKII activity also as potential drug target for post-insult neuroprotection, both after glutamate insults in neuronal cultures and after focal cerebral ischemia in vivo. However, CaMKII and other members of the CaM kinase family have been implicated in regulation of both neuronal death and survival. Here, we discuss past findings and possible mechanisms of CaM kinase functions in excitotoxicity and cerebral ischemia, with a focus on CaMKII and its regulation.

Figure 1

Ischemic core and penumbra after stroke. While neurons in the ischemic core are considered beyond rescue, neurons in the penumbra are potential targets for therapeutic intervention.

Figure 2

The CaM kinase family tree, with a limited number of example CaM kinases marked.

Figure 3

CaMKII structure^, and regulation. (A) CaMKII forms multimeric holoenzymes via C-terminal association domains (acqua). Each kinase domain (grey, dark blue) is stimulated separately by Ca²⁺/CaM binding, but intersubunit autophosphorylation at T286 generates autonomous activity that persists even after dissociation of Ca²⁺/CaM. (B) In the basal state, the regulatory α-helix (ribbon) interacts with the T-site (yellow) and prevents access to the substrate binding S-site (orange). Autophosphorylation sites (red) generate autonomous activity (T286) or prevent CaM binding (T305/306) and affect targeting. (C) The sequence of the regulatory α-helix. The regions contributing to CaM-binding and to auto-inhibition are marked.

Figure 4

CaMKII downstream targets that may be involved in regulation of neuronal viability. CaMKII signaling may promote excitotoxic cell death (red) or neuronal survival (green). Activation (arrow) or inhibition (bar) of the downstream targets is indicated. Some but not all of these downstream effects are mediated by direct phosphorylation of the target.