|Maintenance of Synaptic Strength by CaMKII||Memory|
Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays pivotal roles in synaptic plasticity. It belongs to a class of enzymes called protein kinases that catalyze phosphorylation - addition of a phosphate group (PO43-) to a protein. In biological systems, phosphorylation is commonly used to regulate protein functions.
CaMKII has four different isoforms: α, β, γ and δ. In cells, it does not exist as a monomer, but assembling into a 12-subunit complex known as "holoenzyme" (see this figure). The αCaMKII is the best studied isoform. In this book, the amino acid numbering will be based on αCaMKII. For instance, a crucial residue, threonine (single letter abbreviation: T), is located at the position 286 in the polypeptide chain of αCaMKII, but at 287 in other isoforms. This crucial residue will be denoted by T286, instead of T287.
CaMKII is the major target of Ca2+ ions which enter spines through NMDA receptors (NMDARs) during long-term potentiation (LTP). The Ca2+ ion can bind to calmodulin (a 17 kDa molecule), and the bound complex further binds to each subunit of the CaMKII holoenzyme, triggering autophosphorylation at T286 among CaMKII subunits (Figure 5-1). The phosphorylated CaMKII is persistent active even after the Ca2+ concentration falls to baseline levels. The active CaMKII can then promote AMPAR translocation to the postsynaptic site by phosphorylating AMPAR and stargazin (a 36 kDa protein) (Lisman et al., 2012). As discussed in Chapter 3, increased synaptic AMPAR current enhances EPSP, which facilitates synaptic transmission. However, the AMPAR current is not the only factor that determines synaptic strength. NMDARs also play a crucial role.
Maintenance of Synaptic Strength
Before activation, CaMKII is mostly associated with F-actin (see this figure) which limits the entry of CaMKII into the postsynaptic density (PSD) - a structure just beneath the postsynaptic membrane. Upon activation, the binding between CaMKII and F-actin is disrupted, allowing CaMKII to enter PSD and bind to the GluN2B (also known as NR2B) subunit of NMDAR. The binding between CaMKII and GluN2B further recruits other plasticity related proteins into PSD, such as PSD-95 (see this figure).
The interaction with NR2B locks CaMKII in a persistently active conformation even in the absence of Ca2+/calmodulin binding or autophosphorylation (Bayer et al., 2001). Compelling evidence suggests that synaptic strength is controlled by the amount of CaMKII–NMDAR complex that is present in the synapse (Lisman et al., 2012). Therefore, memory extinction and retrieval should be fundamentally governed by CaMKII and NMDAR.
Author: Frank Lee