PKA-GluA1 coupling via AKAP5 controls AMPA receptor phosphorylation and cell-surface targeting during bidirectional homeostatic plasticity

Bicuculline-induced scaling-down in cultured neurons involves the downregulation of GluA1/2/3 protein levels as well as a reduced synaptic targeting of all AMPAR subunits.

“Bicuculline-induced scaling-down in cultured neurons involves the downregulation of GluA1/2/3 protein levels as well a reduced synaptic targeting of all AMPAR subunits (Diering et al., 2014, Tan et al., 2015).”

TTX-induced homeostatic scaling-up in cultured neurons increases GluA1 protein expression as well as surface and synaptic levels of CP-AMPARs (GluA1 homomers) and GluA1/2 heteromers, but not GluA3-containing AMPARs.

“TTX-induced homeostatic scaling-up in cultured neurons increases GluA1 protein expression as well as surface and synaptic levels of CP-AMPARs (GluA1 homomers) and GluA1/2 heteromers but not in GluA3-containing AMPARs (Figure 3) (Diering et al., 2014, Soares et al., 2013, Tan et al., 2015, Kim and Ziff, 2014, Hu et al., 2010).”

Synaptic GluA1 is dephosphorylated at S831 and S845 during scaling-down and also in the forebrain during sleep.

“Synaptic GluA1 is dephosphorylated at S831 and S845 during scaling-down and also in the forebrain during sleep (Diering et al., 2014, Diering et al., 2017), which together with other observations suggests that homeostatic scaling-down occurs across the forebrain during sleep (Diering et al., 2017).”

Scaling-up involves an increase in phosphorylation of GluA1 S845, but not S831, and is completely blocked in neurons with GluA1 S845A knock-in mutations, but remains intact in GluA1 S831A mutant neurons.

“Scaling-up involves an increase in phosphorylation of GluA1 S845, but not S831, and is completely blocked in neurons with GluA1 S845A knock-in mutations, but remains intact in GluA1 S831A mutant neurons (Diering et al., 2014, Kim and Ziff, 2014).”

Decreased phosphorylation of S845 during scaling-down is not mediated by phosphatase activation, but rather by a decrease in PKA targeting to the synapse through uncoupling with the AKAP5 scaffold, favoring the dephosphorylated state of GluA1.

“Decreased phosphorylation of S845 during scaling-down is not mediated by phosphatase activation, but rather by a decrease in PKA targeting to the synapse through uncoupling with the AKAP5 scaffold, favoring the dephosphorylated state of GluA1 (Figure 3) (Diering et al., 2014).”

GluA1 which remains phosphorylated is resistant to scaling-down, and the unphosphorylated GluA1-containing receptors are preferentially removed.

“Interestingly, GluA1 which remains phosphorylated is resistant to scaling-down and the unphosphorylated GluA1 containing receptors are preferentially removed (Figure 4) (Diering et al., 2014).”