Opposite regulation of inhibitory synaptic plasticity by [alpha] and [beta] subunits of Ca2+/calmodulin-dependent protein kinase II

• Published in: The Journal of physiology Vol. 592; no. 22; p. 4891
• Main Authors: Nagasaki, Nobuhiro, Hirano, Tomoo, Kawaguchi, Shin-ya
• Format: Journal Article
• Language: English
• Published: London Wiley Subscription Services, Inc 01.11.2014
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2014.280230

Key points At inhibitory synapses on a cerebellar Purkinje neuron, depolarization-caused Ca2+ increase induces long-term potentiation (known as rebound potentiation, RP). We show that the subunit composition of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) holoenzyme, consisting of [alpha]- and [beta]CaMKII, is critical for RP induction. [beta]CaMKII plays an essential role in RP induction depending on the high affinity for Ca2+/CaM but not on the F-actin-binding property, whereas [alpha]CaMKII negatively regulates it. [beta]CaMKII enrichment prolongs total CaMKII activation depending on Thr286/287 autophosphorylation. [alpha]- and [beta]CaMKII expression ratio might play critical roles in regulation of synaptic functions in the central nervous system. Induction of several forms of synaptic plasticity, a cellular basis for learning and memory, depends on the activation of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII). CaMKII acts as a holoenzyme consisting of [alpha] and [beta] subunits ([alpha]- and [beta]CaMKII). However, it remains elusive how the subunit composition of a CaMKII holoenzyme affects its activation and hence synaptic plasticity. We addressed this issue by focusing on long-term potentiation (LTP) at inhibitory synapses on cerebellar Purkinje neurons (PNs) (called rebound potentiation, RP). The contribution of each subunit to RP was examined by selective knock-down or overexpression of that subunit. Electrophysiological recording from a rat cultured PN demonstrated that [beta]CaMKII is essential for RP induction, whereas [alpha]CaMKII suppresses it. Thus, RP was negatively regulated due to the greater relative abundance of [alpha]CaMKII compared to [beta]CaMKII, suggesting a critical role of CaMKII subunit composition in RP. The higher affinity of [beta]CaMKII to Ca2+/CaM compared with [alpha]CaMKII was responsible for the predominant role in RP induction. Live-cell imaging of CaMKII activity based on the Förster resonance energy transfer (FRET) technique revealed that [beta]CaMKII enrichment enhances the total CaMKII activation upon a transient conditioning depolarization. Taken together, these findings clarified that [alpha]- and [beta]CaMKII oppositely regulate CaMKII activation, controlling the induction of inhibitory synaptic plasticity in a PN, which might contribute to the adaptive information processing of the cerebellar cortex.