Figure 2

Molecular substrates regulated by PP2A in synaptic plasticity and central sensitization of pain. The auto-phosphorylation of CaMKII triggered by the activation of NMDA receptors is an event critical to the induction of LTP. PP2A is a substrate for CaMKII phosphorylation and the phosphorylated PP2A may decrease the activity of PP2A during LTP. The CaMKII-dependent suppression of PP2A activity and prevention of the de-phosphorylation of CaMKII by PP2A may be necessary for the LTP maintenance. PP2A regulates LTP by competing with PKA for the regulation of specific phosphorylation sites, such as the GluN1 subunits of NMDA receptors. AMPA receptor GluA1 subunit has the two major phosphorylation sites: Ser⁸⁴⁵, which is phosporylated by PKA, and Ser ⁸³¹, which is phosphorylated by PKC. CaMKII was also found to phosphorylate both Ser⁸³¹ and Ser⁸⁴⁵ in GluA1, and contributes to the single-channel conductance of the receptor, and thus, possibly increases AMPA receptor conductance during LTP. The de-phosphorylation of Ser⁸⁴⁵ was blocked by the pretreatment with okadaic acid, indicating an involvement of PP1 and/or PP2A. The phosphorylation or de-phosphorylation of AMPA receptors is closely associated with the receptor trafficking. The GluA1 subunit is the important substrate of PP2A, indicating PP2A activity is a critical for AMPA receptor trafficking and might play an important role in AMPA receptor-mediated nociception. The transcription factor cAMP-response-element-binding protein (CREB) has been demonstrated to be involved in synaptic plasticity and gene transcription and PP2A is thought to be the main CREB phosphatase. Histone deacetylase (HDAC) may reverse the action of histone acetylase and block the gene transcription process through the chromatin remodeling. PP2A is responsible for the de-phosphorylation of class II HDACs and for the subsequent triggering nuclear localization and repression of target genes, while the phosphorylaton-triggering cytoplasmatic localization may lead to the activation of target genes.