Geon Phosphorylation of CaMKII at T305/T306
Causes Synaptic Inhibition
Memory

 

During long-term potentiation (LTP), the Ca2+-bound calmodulin (CaM) binds to each subunit of the CaMKII holoenzyme, resulting in its autophosphorylation at T286, which promotes the interaction with NMDA receptor (NMDAR), thereby locking CaMKII in a persistently active conformation even in the absence of Ca2+/CaM binding or autophosphorylation (Chapter 5). Compelling evidence suggests that synaptic strength increases with increasing number of CaMKII–NMDAR complexes in the synapse (Lisman et al., 2012). However, we know that memory will fade away. What causes memory extinction? More specifically, what causes CaMKII to dissociate from NMDAR? The phosphorylation of CaMKII at T305/T306 may play a key role.

CaMKII Autophosphorylation at T305/T306

In addition to T286, CaMKII can also be autophosphorylated at T305 and/or T306. While phosphorylation at T286 increases synaptic strength, the phosphorylation at T305/T306 causes synaptic depression (Coultrap and Bayer, 2012; Hell, 2014). Therefore, the latter is also known as "inhibitory autophosphorylation", which dramatically decreases the amount of CaMKII within the postsynaptic density (PSD), thus reducing synaptic strength (Elgersma et al., 2002). It has been shown that T305/T306 phosphorylation inhibits CaM-binding and, vice versa, CaM-binding inhibits T305/T306 phosphorylation (Coultrap and Bayer, 2012). Since CaM-binding can trigger autophosphorylation at T286, the two "autonomous states" are mutually exclusive. This is because the autophosphorylation at T305/T306 is regulated by Ca2+/CaM-dependent serine protein kinase (CASK) which competes with CaM for the same binding site on CaMKII.

Regulation by CASK

CASK belongs to the family of membrane-associated guanylate kinases (MAGUK). It contains several different protein–protein binding domains to interact with more than 2 dozen proteins (Hsueh, 2006). The enzyme is implicated in mental retardation (Hsueh, 2009), middle- and long-term memory formation (Malik and Hodge, 2014), and memory extinction (Huang and Hsueh, 2017). In Drosophila, CASK has been demonstrated to induce autophosphorylation of CaMKII at T306 (corresponding to T305 in rat CaMKII mentioned above), block CaM binding and lower the probability of autophosphorylation at T287 (i.e., T286 above) (Hodge et al., 2006).

Image

Figure 6-1. Regulation of CaMKII autophosphorylation. In the absence of CASK, the high Ca2+ concentration stimulates autophosphorylation at T286 which is active. The presence of CASK increases the probability of autophosphorylation at T305/T306 which is inhibitory.

How can autophosphorylation at T305/T306 cause synaptic depression? The long-term depression (LTD) is known to result from AMPAR endocytosis, leading to decrease in synaptic AMPARs. One may suggest that autophosphorylation at T305/T306 would reduce the amount of synaptic AMPARs. Surprisingly, experiments have shown that the inhibitory autophosphorylation can stabilize the synaptic AMPARs at elevated level (Naskar et al., 2014). How can the synapse be depressed while AMPAR level remains high? A novel mechanism is presented in the next chapter.

 

Author: Frank Lee
First Published: September, 2017