LAUSR

Ca2+-calmodulin dependent protein kinase II (CaMKII) assembles into an oligomeric ring in which the kinase domains are organized around a central hub. Notably, the stimulated activity of CaMKII persists even after the withdrawal of a calcium stimulus. CaMKII acquires this Ca2+-independent activity at a threshold frequency and this property is implicated in long-term potentiation (LTP). Indeed, transgenic mice expressing mutant versions of CaMKII have limited LTP and defects in learning and memory. We have previously shown that CaMKII has a remarkable property, which is that activation of CaMKII triggers the exchange of subunits between holoenzymes, including inactive ones, enabling the Ca2+-independent activation of neighboring subunits. Our results have implications for an earlier idea that subunit exchange in CaMKII may have relevance for long-term memory formation. These studies were done using primarily human CaMKIIα, isoform 2. There are four human CaMKII genes, CaMKIIα and β are found in the brain, CaMKIIδ is in the heart, and CaMKIIγ is found throughout the body. Each of these genes has several splice variants encoding ∼20 different isoforms. The primary difference between these isoforms is in the composition and length of the variable linker domain that connects the kinase to the hub. Previous studies have shown that the length of this linker determines the threshold frequency for activation. A comprehensive biochemical study of existing human CaMKII isoforms has not been completed. We have expanded our study of frequency activation and subunit exchange to the remaining isoforms of CaMKII in order to investigate whether these properties are ubiquitous and why specific isoforms are selectively expressed in different cell types. Our new data show that as the variable linker domain is lengthened, less CaM is needed for activation. However, above a certain linker length, there is no added effect.