Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site on GluR1

Abstract

Incorporation of GluR1-containing AMPA receptors into synapses is essential to several forms of neural plasticity, including long-term potentiation (LTP). Numerous signaling pathways that trigger this process have been identified, but the direct modifications of GluR1 that control its incorporation into synapses are unclear. Here, we show that phosphorylation of GluR1 by PKC at a highly conserved serine 818 residue is increased during LTP and critical for LTP expression. GluR1 is phosphorylated by PKC at this site in vitro and in vivo. In addition, acute phosphorylation at GluR1 S818 by PKC, as well as a phosphomimetic mutation, promotes GluR1 synaptic incorporation. Conversely, preventing GluR1 S818 phosphorylation reduces LTP and blocks PKC-driven synaptic incorporation of GluR1. We conclude that the phosphorylation of GluR1 S818 by PKC is a critical event in the plasticity-driven synaptic incorporation of AMPA receptors.

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

“…the MPR or extreme C-terminal region) were deleted. The GFP-A4(22-902; RKR/SSS) with mutated 4.1N/PKCg interaction site was also included, because of the previous evidence suggesting involvement of this region in GluA4 surface expression (Coleman et al, 2003;Boehm et al, 2006).…”

“…The MPR has been previously implicated in GluA4 trafficking (Boehm et al, 2006) and incorporates the established interaction sites for the protein 4.1N (Coleman et al, 2003), PKCγ (Correia et al, 2003), α-actinin-1 and IQGAP1 (Nuriya et al, 2005). The MPR sequence has been reported to promote GluA4 surface expression (Carvalho et al, 1999;Coleman et al, 2003;Gomes et al, 2007;Zheng and Keifer, 2008;2014) as well as phosphorylation by PKCγ at Ser862 (Gomes et al, 2007).…”

“…Consequently, the detailed molecular mechanisms underlying AMPAR and, in particular, GluA4 trafficking at immature synapses are not completely understood. Similar to other types of ionotropic glutamate receptors, synaptic recruitment of GluA4-containing AMPARs is regulated by interactions mediated by its C-terminal domain (CTD; Zhu et al, 2000;Boehm et al, 2006;Luchkina et al, 2014), which is a target for phosphorylation by PKA (Carvalho et al, 1999, Esteban et al, 2003. At GluA4 expressing developing synapses, PKA activation is both necessary and sufficient to drive AMPA receptors to synapses and to produce long-term potentiation (LTP) of synaptic transmission (Zhu et al, 2000;Esteban et al, 2003;Yasuda et al, 2003;Luchkina et al, 2014).…”

Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors

“…One way to alter the function of AMPA receptors is by changing phosphorylation of its subunits. All four subunits of AMPA receptors, GluR1-4, which have several identified phosphorylation sites on their intracellular carboxy-terminus (Song and Huganir, 2002).Among the four subunits, GluR1 has three identified phosphorylation sites, serines 818 (S818) (Boehm et al, 2006), 831 (S831) and 845 (S845) (Roche et al, 1996). S831 is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC), S845 is a cAMP-dependent protein kinase (PKA) substrate (Roche et al, 1996, Barria et al, 1997a, Mammen et al, 1997, while S818 is phosphorylated by PKC (Boehm et al, 2006).…”

“…, Lee et al, 2003. Recent data suggests that S845 and S818 affect the trafficking AMPA receptors to synapses and/or stabilize synaptic AMPA receptors (Esteban et al, 2003, Lee et al, 2003, Boehm et al, 2006. …”