CrossTalk proposal: TARPs modulate AMPA receptor gating transitions

Stargazin promotes closure of the AMPA receptor ligand-binding domain

“…This stabilization could reflect changes in rate constants (decreased CO, increased β; Fig. 2 B ) for transitions between states that exist in the absence of TARPs ( Howe, 2013 ; MacLean, 2013 ), or alternatively result from an effect of TARPs to promote LBD conformations that are inherently more closed and rarely visited in the absence of TARPs. To test this further, we investigated the effect of TARPs on the behavior of antagonists, which do not cause pore opening but retain a ligand-bound pre-open step where the LBD is closed.…”

“…The most parsimonious explanation for these effects is that TARPs reduce the energy barrier for the transitions leading to gating of the channel ( Howe, 2013 ; MacLean, 2013 ). Crystallographic ( Armstrong et al, 2003 ; Jin et al, 2003 ), fluorescence ( Ramanoudjame et al, 2006 ; Gonzalez et al, 2008 ; Ramaswamy et al, 2012 ) and electrophysiological ( Robert et al, 2005 ; Zhang et al, 2008 ) studies have supported the conclusion that the extent to which the ligand-binding domain (LBD) is closed and the stability of the resulting closed-cleft conformations govern the efficacy of a given iGluR agonist.…”

Membrane-tethered AKT kinase regulates basal synaptic transmission and early phase LTP expression by modulation of post-synaptic AMPA receptor level

“…Our bioinformatic analysis using GPS 2.1 (Group‐based Prediction System) software (Xue et al, ) predicted a number of potential AKT‐specific phosphorylation sites on GluR1,2,3 and TARP‐γ8, the major hippocampal TARP (Rouach et al, ) [for review, see (Kato et al, )]. Provided the prediction is true, the phosphorylation of AMPARs and its auxiliary subunits should also affect single channel conductance of the receptor (Cho et al, ; Shelley et al, ; Howe, ), which may, in turn, influence on basal synaptic transmission and eLTP expression. Such a scenario also requires AKT membrane‐tethering, which can be compromised by SC79 application.…”

Rebuttal from David M. MacLean

“…The main effects of the transmembrane AMPA receptor (AMPAR) auxiliary proteins (TARPs) on AMPAR gating are slowing of deactivation and desensitization, increasing peak P open and speeding of recovery from desensitization (Priel et al 2005; Tomita et al 2005). All of these observations can be reproduced by increasing the rate of recovery from desensitization, γ, and by one of two additional means: either increasing the open rate, β (as proposed by Dr Howe, 2013), or reducing the cleft opening rate, CO, and desensitization rate, δ (as suggested by myself, MacLean, 2013). Moreover, increasing the channel opening rate or decreasing the cleft open rate both result in the reported substantial left‐shift in steady‐state glutamate EC 50 values produced by TARPs (Priel et al 2005; Tomita et al 2005; Kott et al 2007) as well as the smaller left‐shift in peak EC 50 values (Morimoto‐Tomita et al 2009).…”