Regulation of AMPA receptor trafficking and exit from the endoplasmic reticulum

Abstract

A fundamental property of the brain is its ability to modify its function in response to its own activity. This ability for self-modification depends to a large extent on synaptic plasticity. It is now appreciated that for excitatory synapses, a significant part of synaptic plasticity depends upon changes in the post synaptic response to glutamate released from nerve terminals. Modification of the post synaptic response depends, in turn, on changes in the abundances of AMPA receptors in the post synaptic membrane. In this review, we consider mechanisms of trafficking of AMPA receptors to and from synapses that take place in the early trafficking stages, starting in the endoplasmic reticulum (ER) and continuing into the secretory pathway. We consider mechanisms of AMPA receptor assembly in the ER, highlighting the role of protein synthesis and the selective properties of specific AMPA receptor subunits, as well as regulation of ER exit, including the roles of chaperones and accessory proteins and the incorporation of AMPA receptors into COPII vesicles. We consider these processes in the context of the mechanism of mGluR LTD and discuss a compelling role for the dendritic ER membrane that is found proximal to synapses. The review illustrates the important, yet little studied, contribution of the early stages of AMPA receptor trafficking to synaptic plasticity.

Figure 1

The dendritic ER is proximal to the plasma membrane due to Homer dimers that link mGluRs at the spines with IP3Rs in the ER. This could enable the insertion of a population of GluA2/3 AMPA receptors directly into the synapse especially upon stimulation of mGluR-LTD. GluA1 homomers are assembled away from the synapse at the somatic ER and inserted into the plasma membrane where they subsequently traffic into the synapse.

Figure 2

mGluR-LTD activates mGluR channels which leads to initiation of protein synthesis and IP3R activation. Protein synthesis leads to accumulation of GluA2 at ERES, while ER Ca²⁺ release leads to CaMKII and PICK1 activation that drives GluA2 containing AMPA receptors (red and yellow) out of the ER via COPII vesicles (green and blue). Accumulation at the ER may involve various AMPA receptor associated proteins (purple) such as stargazin, cornichons, and PICK1.