Geon Tubulin Inhibition Is Regulated by
Protein Kinase A and Calcineurin


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).

More specifically, PKA inhibition decreased the open probability of GluN1/GluN2B but not GluN1/GluN2A receptors (Aman et al., 2014), suggesting that PKA targets GluN2B (formerly NR2B), not GluN2A (NR2A). This result agrees with the finding that PKA associates with GluN2B via the anchoring protein AKAP79/150 (see Chapter 18). The crucial PKA phosphorylation site has been identified as Serine 1166 (S1166), which is distinct from the CaMKII binding region, around 1290-1309 (Strack et al., 2000). 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).

Chapter 11 proposes that the GluN2B-containing NMDARs can be inhibited by tubulin. Experiments have revealed that tubulin binds to the cytoplasmic domain of GluN2B (van Rossum et al., 1999), but the exact binding region was not known. PKA seems to have the capacity to prevent the "extinction state" of GluN2B-containing NMDARs caused by tubulin inhibition. Tubulin is a highly negatively charged protein while phosphorylation is a process that adds a negatively charged phosphate group PO43- to a protein. If tubulin bind to GluN2B around the PKA phosphorylation site, S1166, phosphorylation of this site should disrupt tubulin binding, thereby preventing NMDAR extinction.


Figure 13-1. The crucial sites in the cytoplasmic domain of GluN2B.
(1) S1166 is the target of PKA phosphorylation, which prevents NMDAR inhibition by tubulin. Calcineurin may dephosphorylate S1166, thus promoting tubulin inhibition.
(2) CaMKII binds to the region 1290-1309.
(3) BDNF promotes phosphorylation at Y1472, which prevents GluN2B-containing NMDARs from being internalized, consequently increasing their localization to the membrane (see Chapter 19).

Calcineurin (CaN) catalyzes the dephosphorylation process. It has been shown that CaN competes with PKA for the same site in NMDARs (Raman et al., 1996). While PKA prevents tubulin inhibition of the GluN2B-containing NMDARs, dephosphorylation of S1166 by CaN should have the opposite effects. Indeed, CaN activation has been demonstrated to reduce NMDAR currents (Raman et al., 1996), and play an important role in promoting memory extinction (Lin et al., 2003).

The NMDA plateau has been demonstrated to play a critical role in neuronal firing, particularly for neurons involved in memory storage (Chapter 10). Therefore, memory extinction and retrieval could be fundamentally governed by the NMDA plateau. Silent neurons may result from failure to produce NMDA plateaus. Chapter 11 further shows that binding of tubulin to GluN2B can impede the opening of NMDARs, leading to neuronal silence. Since the binding between tubulin and GluN2B is regulated by PKA and CaN, the following concept is emerging:

Memory extinction and retrieval could be regulated by the competition between PKA and CaN for the phosphorylation state of S1166. Phosphorylation of S1166 by PKA facilitates retrieval whereas dephosphorylation of S1166 by CaN promotes extinction.


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