α- and βCaMKII Inverse Regulation by Neuronal Activity and Opposing Effects on Synaptic Strength

to the catalytic sites in the basal state. The binding of Ca 2ϩ /calmodulin releases this autoinhibition, allowing phosphorylation to take place at a critical threonine resi-a property that endows CaMKII with the ability Summary to decode Ca 2ϩ signals in a frequency-dependent man-We show that ␣ and ␤CaMKII are inversely regulated Schulman et al., 1992; see also Eshete and Fields, 2001). by activity in hippocampal neurons in culture: the ␣/␤ Immunoprecipitation with subunit-specific antibodies ratio shifts toward ␣ during increased activity and ␤ indicates that the majority of the CaMKII holoenzymes during decreased activity. The swing in ratio is ‫-5ف‬fold are ␣/␤ heteromers with variable subunit ratios, although and may help tune the CaMKII holoenzyme to chang-some ␣ homomers can also be found (Bennett et al., ing intensities of Ca 2؉ signaling. CaMKII levels uses distinguishable pathways, one re-have two isoforms? One significant distinction between sponsive to NMDA receptor blockade that controls the ␣ and ␤ isoforms lies in their sharply different affinity ␣CaMKII alone, the other responsive to AMPA recep-for calmodulin. Half-maximal autophosphorylation is tor blockade and involving ␤CaMKII and possibly fur-achieved at 130 nM calmodulin for ␣CaMKII and at 15 ther downstream effects of ␤CaMKII on ␣CaMKII. nM calmodulin for ␤CaMKII (Brocke et al., 1999). Due Overexpression of ␣CaMKII or ␤CaMKII resulted in to this difference, the two isoforms have different sensi-opposing effects on unitary synaptic strength as tivities to Ca 2ϩ signals under nonsaturating levels of well as mEPSC frequency that could account in part calmodulin. ␣CaMKII is selective for higher levels of Ca 2ϩ for activity-dependent effects observed with chronic signals, while ␤CaMKII has better sensitivity to lower blockade of AMPA receptors. Regulation of CaMKII levels of signal. When the two isoforms are combined subunit composition may be important for both activ-in a heteromer, the response to Ca 2ϩ signals has been ity-dependent synaptic homeostasis and plasticity.Introduction quently, activity-dependent regulation of ␣-and ␤CaM-KII expression could provide a mechanism of tuning Calcium/calmodulin-dependent protein kinase II (CaM-neuronal responses to different levels of activity. This is KII) is expressed at high levels in the central nervous an intriguing possibility that raises several fundamental system (Bennett et al., 1983), particularly in the hippo-questions. Does the cell regulate the ratio of ␣ to ␤ in an campus, where it constitutes ‫%2ف‬ of total protein activity-dependent manner? And if so, what pathways of (Erondu and Kennedy, 1985). Highly enriched in the …