Calcium-Permeable AMPA Receptor Plasticity Is Mediated by Subunit-Specific Interactions with PICK1 and NSF

Abstract

A recently described form of synaptic plasticity results in dynamic changes in the calcium permeability of synaptic AMPA receptors. Since the AMPA receptor GluR2 subunit confers calcium permeability, this plasticity is thought to occur through the dynamic exchange of synaptic GluR2-lacking and GluR2-containing receptors. To investigate the molecular mechanisms underlying this calcium-permeable AMPA receptor plasticity (CARP), we examined whether AMPA receptor exchange was mediated by subunit-specific protein-protein interactions. We found that two GluR2-interacting proteins, the PDZ domain-containing Protein interacting with C kinase (PICK1) and N-ethylmaleimide sensitive fusion protein (NSF), are specifically required for CARP. Furthermore, PICK1, but not NSF, regulates the formation of extrasynaptic plasma membrane pools of GluR2-containing receptors that may be laterally mobilized into synapses during CARP. These results demonstrate that PICK1 and NSF dynamically regulate the synaptic delivery of GluR2-containing receptors during CARP and thus regulate the calcium permeability of AMPA receptors at excitatory synapses.

Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications

“…Alternatively, synaptic activity may be required to maintain GluR2 subunits, and absence of activity results in switching to GluR2-lacking AMPARs (SI Text, Note 4). Switching from GluR2-lacking to GluR2-containing requires interactions between GluR2 and NSF, GluR2, and PICK1/GRIP in the cerebellar stellate cells (27,28). PICK1 also plays a critical role in subunit switch in the hippocampal CA1 neurons (26).…”

Synaptic AMPA receptor composition in development, plasticity and disease

“…Given that synaptic CP-AMPARs in stellate cells have been suggested to be GluA3 homomers 45 , this implies specific regulation of the interaction of GRIP1 with GluA2 versus GluA3 and further work will be required to define how this is achieved. The multimeric ATPase NSF has also been implicated in stellate cell plasticity 105 . NSF interacts with GluA2 and blockade of the GluA2-NSF interaction results in a rapid rundown in AMPAR EPSCs, supporting a role for NSF in constitutive cycling of GluA2-containing AMPARs 107 .…”

“…5). Despite this process being the reverse of that observed during hippocampal LTP, PICK1 is also required for this form of plasticity 104,105 . In contrast to its proposed role in restricting surface expression of GluA2-containing AMPARs during hippocampal LTP, PICK1 promotes the CP-to CI-AMPAR switch in stellate cells by supporting an extrasynaptic pool of 8 GluA2-containing receptors, although the molecular mechanisms underlying this effect are unclear.…”

Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells

“…This requires activation of either synaptic Ca 2ϩ -permeable AMPARs or extrasynaptic N-methyl-D-aspartate receptors (NMDARs) (Gardner et al 2005;CullCandy 2000, 2005;Sun and Liu 2007). Activation of metabotropic receptors can also alter synaptic AMPAR subtype in a protein synthesis-dependent manner (Kelly et al 2009).…”