Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, γ-5

Abstract

Although the properties and trafficking of AMPA-type glutamate receptors (AMPARs) depend critically on associated transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2), no TARP has been described that can specifically regulate the important class of calciumpermeable (CP-) AMPARs. We examined the stargazin-related protein γ-5, which is highly expressed in Bergmann glia, a cell type possessing only CP-AMPARs. γ-5 was previously thought not to be a TARP, and it has been widely used as a negative control. Here we find that, contrary to expectation, γ-5 acts as a TARP and serves this role in Bergmann glia. Whereas, γ-5 interacts with all AMPAR subunits, and modifies their behavior to varying extents, its main effect is to regulate the function of AMPAR subunit combinations that lack short-form subunits, which constitute predominantly CP-AMPARs. Our results suggest an important role γ-5 in regulating the functional contribution of CP-AMPARs.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…The functional properties of AMPA receptors associated with the TARP subtypes ␥-2, ␥-3, ␥-4, and ␥-8 are different from those of AMPA receptors devoid of auxiliary subunits. In addition to their trafficking capabilities, TARPs increase single channel conductance, increase open probability, increase the activation rate, slow the deactivation time course, and reduce desensitization (Yamazaki et al, 2004;Priel et al, 2005;Tomita et al, 2005a;Turetsky et al, 2005;Zhang et al, 2006b;Kato et al, 2007;Soto et al, 2007Soto et al, , 2009. Prolonged activation of AMPA receptors triggers a form of desensitization that results from dissociation of the TARP, potentially providing a novel mechanism for receptor tuning (Morimoto-Tomita et al, 2009).…”

Synaptic AMPA receptor composition in development, plasticity and disease

“…Thus, in addition to their well-characterised role in determining the biophysical properties of AMPARs, TARPs also play a key role in synaptic AMPAR retention under basal and activity-dependent conditions. Beyond the synaptic trapping of AMPARs, the TARPs Stargazin and γ5 directly reduce the polyamine sensitivity of CP-AMPARs 121,122 . Because polyamine block is a parameter used to determine the GluA2 content of the receptors, the presence or absence of TARPs can therefore complicate unambiguous determination of subunit content and necessitates careful consideration of the role of TARPs in the trafficking of CP-versus CI-AMPARs.…”

Stargazin-related protein γ7 is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth

“…Some members of the family of -subunits or TARPs have 2052 Journal of Cell Science 124 (12) been shown to have a role in AMPA receptor function (Tomita et al, 2003). Despite not having a classical C-terminal PDZ motif,  7 has also recently been shown to have effects on AMPA receptor trafficking (Kato et al, 2007), and  5 has been found to affect Ca 2+ -permeable AMPA receptors in Bergmann glia (Soto et al, 2009). Nevertheless, in a recent proteomic study, only a small proportion of AMPA receptors were found to be associated with  subunits, with  5 and  7 being particularly rare (Schwenk et al, 2009), despite the fact that  7 is widely expressed in brain (Moss et al, 2002).…”