คาสิโนไทย NMDAR Extinction Is Regulated by Protein Kinase A Memory

 

It has been known for over two decades that protein kinase A (PKA) regulates the Ca2+ influx through NMDA receptors (NMDARs):

  1. The NMDAR-mediated excitatory postsynaptic currents (EPSCs) were enhanced by PKA phosphorylation (Raman et al., 1996).
  2. PKA blockers markedly inhibited NMDAR-mediated Ca2+ rises (Skeberdis et al., 2006).
  3. PKA inhibition lengthened the closed duration of GluN2B- but not GluN2A-containing NMDARs (Aman et al., 2014), suggesting that PKA targets GluN2B (formerly NR2B), not GluN2A (NR2A).

Aman et al. referred to the PKA-dependent closed state as "desensitized state", which is identical to the extinction state described in the previous chapter. This closed state is called the "extinction state" because it could give rise to memory extinction (inhibition of memory retrieval) based on mounting evidence that PKA can influence memory extinction (Koh et al., 2002; Isiegas et al., 2006; คาสิโนไทยMueller et al., 2008; Nijholt et al., 2008; Menezes et al., 2015). The previous chapter further shows that the extinction state of NMDAR could be caused by the binding between the C-terminal domain (CTD) of GluN2B and the CABT complex which consists of a CRMP2 monomer and a tubulin heterodimer.

PKA is an enzyme that catalyzes protein phosphorylation - addition of a phosphate group PO43-. The crucial PKA phosphorylation site has been identified as Serine 1166 (S1166) located in the CTD of the GluN2B subunit. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca2+ permeation, synaptic currents, and Ca2+ rises in dendritic spines (Murphy et al., 2014). These results support the notion that PKA could regulate the inhibition of GluN2B-containing NMDARs by the CABT complex,

By analyzing the amino acid sequence of the GluN2B CTD, it was found that the CTD is intrinsically disordered, but may switch dynamically between folded and unfolded conformation (Ryan et al., 2008). Since PKA plays a crucial role in NMDAR extinction, it is reasonable to assume that the dynamic switch between folded and unfolded conformation could be controlled by PKA phosphorylation. The unfolded conformation, as shown in Figures 12-1, may associate with CABT, resulting in NMDAR extinction, whereas the folded conformation could prevent CABT-GluN2B binding.

The effect of PKA on the Ca2+ influx through NMDARs indicates that phosphorylation of S1166 may prevent CABT-GluN2B binding, thereby reducing NMDAR closure. This in turn suggests that S1166 phosphorylation could promote a folded conformation to block DWED-H19 interaction. The folded conformation is proposed in Figure 13-1, where DWED is buried within the GluN2B CTD, unable to interact with H19. It is important to note that, for PKA to regulate conformational switch, DWED should be in close proximity to S1166. This can be achieved by two turns: one at GGGP (residues 1169 - 1172) and another at GGVP (residues 1191 - 1194). Hence, this model is consistent with the fact that glycine (G) and proline (P) residues are frequently found in turn and loop structures of proteins (Krieger et al., 2005).

Image

Figure 13-1. The proposed folded conformation of residues 1161 - 1210 in the GluN2B CTD. The upper and lower segments in (A) should be on the same plane such that the residues DFKRDS may interact with DWEDRS as shown in (B). The middle segment in (A) should be on a different plane to avoid interference with DFKRDS - DWEDRS interaction. It is omitted in (B) for clarity.

The attractive interaction between a phosphate group and an arginine residue is very strong (คาสิโนไทย). In Figure 13-1B, there is an arginine that may interact with S1166. It is assumed that the phosphorylation state of S1166 is sufficient to control the switch between folded and unfolded conformation of the GluN2B CTD. Phosphorylation at S1166 could stabilize the folded structure, preventing CABT-GluN2B binding, consequently enhancing the Ca2+ influx through GluN2B-containing NMDARs. This notion is supported by a growing number of studies demonstrating that the arginine-rich peptides can enhance memory extinction and alleviate NMDAR-mediated excitotoxicity, possibly by blocking the DFKRDS - DWEDRS interaction to promote unfolded conformation (more info).

 

Author: Frank Lee
First Published: November, 2017
Last updated: May, 2018