CAMK1G, Active

CLICK-III/CaMKIG is a novel membrane-anchored neuronal Ca2+/calmodulin-dependent protein kinase (CaMK), an isoform of the CaMKI family with an extended C-terminal domain ending with CAAX motif (where AA is aliphatic acid). As expected from the similarity of its kinase domain with the other CaMKI isoforms, full activation of CLICK-III/CaMKIG required both Ca(2+)/CaM and phosphorylation by CaMKK. Ca(2+)/cAMP-response element-binding protein (CREB) was a good substrate for CLICK-III/CaMKIG, at least in vitro. Interestingly enough, CLICK-III/CaMKIG transcripts were most abundant in neurons, with the highest levels in limited nuclei such as the central nucleus of the amygdala (CeA) and the ventromedial hypothalamus. Consistent with the presence of the CAAX motif, CLICK-III/CaMKIG was found to be anchored to various membrane compartments, especially to Golgi and plasma membranes. Both point mutation in the CAAX motif and treatment with compactin, a HMG-CoA reductase inhibitor, disrupted such membrane localization, suggesting that membrane localization of CLICK-III/CaMKIG occurred in a prenylation-dependent way. These findings provide a novel mechanism by which neuronal CaMK activity could be targeted to specific membrane compartments.