Opposite regulation of inhibitory synaptic plasticity by α and β subunits of Ca2+/calmodulin‐dependent protein kinase II

• Published in: The Journal of physiology Vol. 592; no. 22; pp. 4891 - 4909
• Main Authors: Nagasaki, Nobuhiro, Hirano, Tomoo, Kawaguchi, Shin‐ya
• Format: Journal Article
• Language: English
• Published: Oxford, UK BlackWell Publishing Ltd 15.11.2014
• Subjects: Neuroscience: Cellular/Molecular
• 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 α‐ and βCaMKII, is critical for RP induction. βCaMKII plays an essential role in RP induction depending on the high affinity for Ca2+/CaM but not on the F‐actin‐binding property, whereas αCaMKII negatively regulates it. βCaMKII enrichment prolongs total CaMKII activation depending on Thr286/287 autophosphorylation. α‐ and βCaMKII 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 α and β subunits (α‐ and βCaMKII). 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 βCaMKII is essential for RP induction, whereas αCaMKII suppresses it. Thus, RP was negatively regulated due to the greater relative abundance of αCaMKII compared to βCaMKII, suggesting a critical role of CaMKII subunit composition in RP. The higher affinity of βCaMKII to Ca2+/CaM compared with αCaMKII 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 βCaMKII enrichment enhances the total CaMKII activation upon a transient conditioning depolarization. Taken together, these findings clarified that α‐ and βCaMKII 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.