The GHB analogue HOCPCA improves sensorimotor function after MCAO via CaMKIIα

Abstract

Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented GHB ligands as the first small molecules selectively targeting the CaMKII hub, a domain primarily responsible for holoenzyme oligomerisation, with an emerging functional role. Here, we report that the GHB ligand, HOCPCA, improves sensorimotor function after experimental stroke in mice when administered at clinically relevant time and in combination with alteplase. We observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated the ischemia-specific expression of a constitutively active CaMKII kinase fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. HOCPCAs selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKII hub domain as an attractive neuroprotective strategy.