CaMKIIα as a Promising Drug Target for Ischemic Grey Matter

Abstract

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of Ca2+-dependent signaling pathways in various cell types throughout the body. Its neuronal isoform CaMKIIa (alpha) centrally integrates physiological but also pathological glutamate signals directly downstream of glutamate receptors and has thus emerged as a target for ischemic stroke. Previous studies provided evidence for the involvement of CaMKII activity in ischemic cell death by showing that CaMKII inhibition affords substantial neuroprotection. However, broad inhibition of this central kinase is challenging because various essential physiological processes like synaptic plasticity rely on intact CaMKII regulation. Thus, specific strategies for targeting CaMKII after ischemia are warranted which would ideally only interfere with pathological activity of CaMKII. This review highlights recent advances in the understanding of how ischemia affects CaMKII and how pathospecific pharmacological targeting of CaMKII signaling could be achieved. Specifically, we discuss direct targeting of CaMKII kinase activity with peptide inhibitors versus indirect targeting of the association (hub) domain of CaMKIIa with analogues of g-hydroxybutyrate (GHB) as a potential way to achieve more specific pharmacological modulation of CaMKII activity after ischemia.

Calcium-Associated Proteins in Neuroregeneration

“…Previous reports have demonstrated evidence supporting the role of CaMKII activity in ischemic cell death, indicating that substantial neuroprotection can be achieved by inhibiting CaMKII. However, the broad inhibition of this pivotal kinase is challenging due to its involvement in various physiological processes like synap-tic plasticity [55]. It was detected that the constitutive knockout of CaMKIIα provided protection against neuronal cell death following global cerebral ischemia in mice.…”

“…The upregulation of these CaMKII kinases activates the NF-κB signaling pathway, ensuring neuroprotection against ischemic injuries [58]. For a more in-depth understanding of the role of CaMKII in cerebral ischemia and its potential as a pharmacological target, readers are referred to [55,57].…”