Regulation of AMPA receptors in spinal nociception

Abstract

The functional properties of alpha-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptors in different brain regions, such as hippocampus and cerebellum, have been well studied in vitro and in vivo. The AMPA receptors present a unique characteristic in the mechanisms of subunit regulation during LTP (long-term potentiation) and LTD (long-term depression), which are involved in the trafficking, altered composition and phosphorylation of AMPA receptor subunits. Accumulated data have demonstrated that spinal AMPA receptors play a critical role in the mechanism of both acute and persistent pain. However, less is known about the biochemical regulation of AMPA receptor subunits in the spinal cord in response to painful stimuli. Recent studies have shown that some important regulatory processes, such as the trafficking of AMPA receptor subunit, subunit compositional changes, phosphorylation of AMPA receptor subunits, and their interaction with partner proteins may contribute to spinal nociceptive transmission. Of all these regulation processes, the phosphorylation of AMPA receptor subunits is the most important since it may trigger or affect other cellular processes. Therefore, these study results may suggest an effective strategy in developing novel analgesics targeting AMPA receptor subunit regulation that may be useful in treating persistent and chronic pain without unacceptable side effects in the clinics.

Figure 1

Pathways of AMPA receptor trafficking. AMPA receptors may cycle between intracellular stores and the cell surface rapidly and constitutively. AMPA receptors in plasma membrane may exchange between the extra-synaptic and synaptic membrane in a manner of lateral diffusion. The receptor-cycling event and lateral diffusion can regulate the number of AMPA receptors in synapses and further changes the synapse strength. PSD, post-synaptic density.

Figure 2

The phosphorylation of AMPA receptor subunits and its interaction with partner proteins in spinal neurons. In spinal neurons, it has shown that PKA mediates the phosphorylation of serine at the Serine⁸⁴⁵ site, and PKC targets the Serine⁸³¹ site following noxious stimulation. More specifically, CaMKII mediates the phosphorylation of GluR1 subunit of AMPA receptor at both Serine⁸³¹ and Serine⁸⁴⁵ sites in spinal neurons after strong noxious peripheral stimulation. GluR2 subunits of AMPA receptors may bind to GRIP and PICK1, which play an important role in the GluR2 trafficking. GRIP anchors GluR2 subunits at synapses, whereas PICK1 brings PKC to synaptic GluR2. PKC phosphorylates GluR2 Serine⁸⁸⁰ to release GluR2 from GRIP and to promote GluR2 internalization. CFA-induced peripheral inflammation could induce GluR2 internalization in dorsal horn neurons. Stargazin binds to GluR1, 2, and 4. Binding of the Stargazin C-terminal tail to PSD-95 mediates the synaptic targeting of surface AMPA receptors. SAP 97 binds to the GluR1 C-terminus, interacts with the actin-associated protein 4.1N and is implicated in GluR1 synaptic insertion. NSF protein plays a role in membrane fusion processes and also interacts with GluR2 and GluR3 subunits of AMPA receptors. The following abbreviations are used: PKA, protein kinase A; PKC, protein kinase C; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; GRIP, glutamate receptor interacting protein; PICK1, protein interacting with C-Kinase; CFA, complete Freund Adjuvant; TARP, transmembrane AMPA receptor regulatory proteins; PDZ, postsynaptic density zone; PSD, postsynaptic density; SAP 97, synapse-associated protein 97; NSF, N-ethylmaleimide sensitive fusion.