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.

Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway

“…It is believed that CaMKIIδ and CaMKIIγ are ubiquitously distributed, but their levels in the brain are much lower than CaMKIIα and CaMKIIβ [3,[17][18][19]. Therefore, CaMKIIδ and CaMKIIγ have received less attention in the neuronal system.…”

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

“…Nonetheless, as is the case for many other signaling kinase systems, CaMKII is associated with the regulation of both neuroprotective and neurodestructive cellular signaling pathways (65,66). As such, inhibiting kinase activity is likely to be a poor candidate approach for translational therapeutic studies.…”

Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders

“…Alternatively, cell-permeable peptides that mimic endogenous inhibitors of STEP may provide a degree of isoform specificity. There is precedence for this technology; tatCN21, a potent and selective inhibitor of CaMKII derived from the natural CaMKII inhibitor CaM-KIIN, has no effect on the activity of CaMKI, CaMKIV, or CaMKK (Coultrap et al, 2011). Largescale screenings to identify and characterize potential endogenous proteins that interact with and modulate STEP activity will be necessary to move this possibility forward.…”