Research Article: Analysis of the Potential Role of GluA4 Carboxyl-Terminus in PDZ Interactions

Date Published: January 14, 2010

Publisher: Public Library of Science

Author(s): Sarah K. Coleman, Chunlin Cai, Nisse Kalkkinen, Esa R. Korpi, Kari Keinänen, Lin Mei.

Abstract: Specific delivery to synapses of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors with long-tailed subunits is believed to be a key event in many forms of activity-dependent changes in synaptic strength. GluA1, the best characterized long-tailed AMPA receptor subunit, contains a C-terminal class I PDZ binding motif, which mediates its interaction with scaffold and trafficking proteins, including synapse-associated protein 97 (SAP97). In GluA4, another long-tailed subunit implicated in synaptic plasticity, the PDZ motif is blocked by a single proline residue. This feature is highly conserved in vertebrates, whereas the closest invertebrate homologs of GluA4 have a canonical class I PDZ binding motif. In this work, we have examined the role of GluA4 in PDZ interactions.

Partial Text: AMPA receptors mediate the majority of mammalian fast excitatory neurotransmission and play important roles in synaptic plasticity. AMPA receptors are tetramers composed of various combinations of four homologous subunits GluA1 to 4 (alternatively GluR-A to -D, or GluR1-4). The number and subunit composition are important determinants of synaptic strength. Subunit-specific AMPA receptor trafficking is largely governed by the cytoplasmic C-terminal tails (CTDs) (reviewed in [1], [2]); with the specific activity-dependent insertion of the long-tailed (70–80 residues) subunits GluA1, GluA2L (minor isoform) and GluA4 occuring in various forms of synaptic plasticity, leading to enhanced AMPA receptor responses [3]–[7].

The sequence similarities in the CTDs of the long-tailed AMPA receptor subunits are illustrated in Figure 1. In rat GluA4 and GluA2L, the residues corresponding to the class I PDZ motif in GluA1 are conserved, but followed by a single “blocking” residue (Figure 1A). The extreme carboxyterminal tetrapeptide sequence, including the cryptic PDZ motif and the blocking residue, are absolutely conserved in GluA4 orthologs representing widely disparate vertebrate lineages (Figure 1B). This is consistent with important function(s), most likely, C-terminus -dependent protein interactions, but none such are known. The carboxyl-terminal tail of GluA2L shows a similar high degree of sequence conservation (Figure S1). Interestingly, the invertebrate homologs showing the closest similarity to GluA4 C-terminus have a genuine class I PDZ motif with no blocking residue (Figure 1C). Importantly, the sequence pattern KARLS/T, a distinguishing feature of GluA2L and A4 subunits as opposed to GluA1, is present in the invertebrate sequences, arguing for a closer kinship to GluA4/2L. These findings raise the possibility that the blocking residue in vertebrate “non-GluA1” long-tailed AMPA receptor subunits may have evolved to faciliate its regulated exposure to PDZ interactions.



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