|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):
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.
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:
Author: Frank Lee