|คาสิโนไทย||The Role of CaMKII in Synaptic Plasticity||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 (abbreviated as 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.
During the induction of long-term potentiation (LTP), the Ca2+ influx through NMDARs may target several enzymes, including CaMKII. As the name implies, activation of CaMKII depends on the bound Ca2+/calmodulin complex. Calmodulin is a 17 kDa protein which, upon association with Ca2+, may bind 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) (คาสิโนไทยHell, 2014). As discussed in Chapter 3, increased synaptic AMPAR current enhances EPSP, facilitating synaptic transmission.
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 (formerly NR2B) subunit of NMDAR. The binding between CaMKII and GluN2B further recruits other plasticity related proteins into PSD, such as PSD-95.
The interaction with GluN2B locks CaMKII in a persistently active conformation even in the absence of Ca2+/calmodulin binding or autophosphorylation (Bayer et al., 2001). This led to the assumption that synaptic strength might be stored stably in the CaMKII/NMDAR complex (Sanhueza and Lisman, 2013). The hypothesis, however, faces several challenges:
Accumulating evidence suggests that the synaptic strength is stored in the synaptic AMPARs. Within 1 month after LTP induction, the level of synaptic AMPARs could be maintained primarily by atypical protein kinase C, such as PKMζ and PKCι/λ (see this chapter).
Author: Frank Lee