Geon Structural Insights into
the Regulation of NMDA Receptors by CRMP2



Mounting evidence revealed that protein kinase A (PKA) could influence memory extinction (inhibition of memory retrieval), but the underlying mechanism remains elusive. PKA antagonists may lengthen the closed duration of GluN2B- but not GluN2A-containing NMDA receptors (NMDARs), as demonstrated by Aman et al. (2014) who refer to the PKA-dependent closed state as "desensitized state". Since this state could give rise to memory extinction, it will be called the "extinction state". This paper shows that the extinction state of NMDARs could be caused by the binding between the C-terminal domain (CTD) of GluN2B and the CABT complex, which consists of a CRMP2 monomer, alpha (α) and beta (β) tubulin. In the unfolded conformation of CTD, CABT may bind to GluN2B and occlude the ion-conducting pore of GluN2B-containing NMDARs, whereas a folded conformation prevents the CABT-GluN2B binding, thereby enhancing the Ca2+ influx through NMDARs. The conformational switch is regulated by PKA phosphorylation. Since the attractive interaction between a phosphate group and arginine is very strong (Woods and Ferré, 2005), this model also explains why arginine-rich peptides can attenuate NMDAR activity and enhance memory extinction.


Read Online Download PDF