Stargazin Reduces Desensitization and Slows Deactivation of the AMPA-Type Glutamate Receptors

Abstract

The AMPA-type glutamate receptors mediate the majority of the fast excitatory synaptic transmission and critically contribute to synaptic plasticity in the brain, hence the existence of numerous trafficking proteins dedicated to regulation of their synaptic delivery and turnover. Stargazin (also termed ␥2) is a member of a recently identified protein family termed transmembrane AMPA receptor regulatory proteins (TARPs). TARPs physically associate with AMPA receptors and participate in their surface delivery and anchoring at the postsynaptic membrane. Here, we report that next to its trafficking roles, stargazin may also act as a positive allosteric modulator of AMPA receptor ion channel function. Coexpression of stargazin with AMPA receptor subunits, either in Xenopus oocytes or in human embryonic kidney 293 cells, significantly reduced receptor desensitization in response to glutamate. Receptor deactivation rates were also slowed, and the recovery from desensitization was accelerated. Structurally, based on the data showing a tight correlation between desensitization and the stability of the AMPA receptor intradimer interface, we propose that binding of stargazin may stabilize the receptor conformation. Functionally, our data suggest that AMPA receptors complexed with stargazin (and possibly also with other TARPs) at the postsynaptic membrane are significantly more responsive to synaptically released glutamate compared with AMPA receptors lacking stargazin/TARP interaction. The putative existence of such two states of synaptic AMPA receptors, with and without stargazin/TARP binding, may provide a novel mechanism for regulation of excitatory synaptic strength during development and/or in synaptic plasticity in the adult brain.

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

“…Previous studies showed that ␥-2 increases the potency of glutamate for GluR1 (Priel et al, 2005;Tomita et al, 2005b). Similarly, we find that cotransfection of ␥-2 shifts the doseresponse curve for glutamate to the left and increases the EC 50 by threefold.…”

“…␥-2 slows both the deactivation and desensitization of associated AMPA receptors (Priel et al, 2005;Tomita et al, 2005b). To determine whether ␥-7 also alters channel gating, we expressed GluR1 alone and in the presence of ␥-2, ␥-5, or ␥-7 in HEK293T cells (Fig.…”

“…The C-terminal tail of stargazin associates with postsynaptic density-95 (PSD-95) and related membrane-associated guanylate kinase proteins, which cluster AMPA receptors at synapses (El-Husseini et al, 2000;Schnell et al, 2002;Elias et al, 2006) The first extracellular loop of stargazin associates with the glutamate-binding module in AMPA receptors (Tomita et al, 2006b) and thereby modulates channel gating and pharmacology (Yamazaki et al, 2004;Turetsky et al, 2005;Bedoukian et al, 2006;Tomita et al, 2006a). Stargazin delays deactivation and desensitization of AMPA receptors (Priel et al, 2005;Tomita et al, 2005b), enhances the action of kainate on AMPA receptors (Tomita et al, 2005b;Turetsky et al, 2005), and modulates the effects of AMPA receptor potentiators, such as cyclothiazide (Tomita et al, 2006a;Zhang et al, 2006). Phosphorylation of stargazin regulates AMPA receptors in synaptic plasticity (Tomita et al, 2005a).…”

Structural Basis for Spinophilin−Neurabin Receptor Interaction

“…The C-termini of these receptor subunits are especially critical for the regulation of AMPA receptor function. While it is widely recognized that AMPA receptor function is highly complex, including important regulatory effects due to receptor trafficking (42,43) and interactions with additional membrane proteins, such as stargazin (44)(45)(46), it is evident that the phosphorylation state of Ser845 on GluR1 subunits is one of the most important factors for regulation of AMPAreceptor activity (47). For example, using a S845A mutant, it has been shown that phosphorylation of Ser845 results in a dramatic potentiation of channel activity in response to glutamate (48).…”

Regulation of AMPA receptors and synaptic plasticity

“…In addition to the effect on AMPAR trafficking, Stargazin controls AMPAR channel gating by slowing glutamateinduced AMPAR deactivation and desensitization, and enhancing the channel conductance (Priel et al, 2005;Tomita et al, 2005;Nicoll et al, 2006). Moreover, in the presence of TARPs, the AMPARs competitive antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) acts as a partial agonist (Menuz et al, 2007).…”