Abstract
The GluA2 subunit of the AMPA receptor (AMPAR) dominantly blocks AMPAR Ca(2+) permeability, and its trafficking to the synapse regulates AMPAR-dependent synapse Ca(2+) permeability. Here we show that GluA2 trafficking from the endoplasmic reticulum (ER) to the plasma membrane of cultured hippocampal neurons requires Ca(2+) release from internal stores, the activity of Ca(2+)/calmodulin activated kinase II (CaMKII), and GluA2 interaction with the PDZ protein, PICK1. We show that upon Ca(2+) release from the ER via the IP3 and ryanodine receptors, CaMKII that is activated enters a complex that contains PICK1, dependent upon the PICK1 BAR (Bin-amphiphysin-Rvs) domain, and that interacts with the GluA2 C-terminal domain and stimulates GluA2 ER exit and surface trafficking. This study reveals a novel mechanism of regulation of trafficking of GluA2-containing receptors to the surface under the control of intracellular Ca(2+) dynamics and CaMKII activity.
Highlights
endoplasmic reticulum (ER) exit is a rate-limiting step for GluA2 synaptic delivery, which regulates AMPA receptor (AMPAR) trafficking and synaptic calcium dynamics
calmodulin activated kinase II (CaMKII) Is Required for GluA2 Trafficking to the Surface in Hippocampal Cultures—To test the roles of protein kinases in GluA2 surface trafficking, we measured the effects of various protein kinase inhibitors on GluA2 levels in the plasma membrane of cultured embryonic hippocampal neurons (17–21 days in vitro (DIV))
PICK1-dependent GluA2 Trafficking to Neuronal Surface— We have previously shown that the exit of GluA2 from the ER depends on the PICK1 protein [7], a Ca2ϩ-responsive, PDZ protein that binds the GluA2 C-terminal domain and mobilizes trafficking of GluA2 [28, 32,33,34,35]
Summary
ER exit is a rate-limiting step for GluA2 synaptic delivery, which regulates AMPAR trafficking and synaptic calcium dynamics. We show that upon Ca2؉ release from the ER via the IP3 and ryanodine receptors, CaMKII that is activated enters a complex that contains PICK1, dependent upon the PICK1 BAR (Bin-amphiphysin-Rvs) domain, and that interacts with the GluA2 C-terminal domain and stimulates GluA2 ER exit and surface trafficking. This study reveals a novel mechanism of regulation of trafficking of GluA2-containing receptors to the surface under the control of intracellular Ca2؉ dynamics and CaMKII activity. We found that release of Ca2ϩ from the ER via the IP3 and ryanodine receptors activates CaMKII, which enters a complex that contains PICK1 Association of this complex with GluA2 stimulates GluA2 exit from the ER leading to trafficking to the plasma membrane. We suggest that this pathway acts as a feedback mechanism to limit Ca2ϩ influx through Ca2ϩ-permeable AMPARs
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