Coexpressed Auxiliary Subunits Exhibit Distinct Modulatory Profiles on AMPA Receptor Function

Abstract

Gating properties and surface trafficking of AMPA receptors (AMPARs) are modulated by auxiliary subunits. Here we studied the function of coexpressed auxiliary subunits belonging to two different classes. We focused on TARP γ-8 and CKAMP44 in dentate gyrus (DG) granule cells, since both subunits are highly expressed in this cell type. TARP γ-8 and CKAMP44 decrease the rate of deactivation but have an opposing influence on receptor desensitization, which accounts for their differential modulation of synaptic short-term plasticity. Furthermore, long-term plasticity (LTP) requires TARP γ-8 but not CKAMP44. The coexpression of both auxiliary subunits is necessary for the efficient targeting of AMPARs to the cell surface of DG granule cells. Finally, electrophysiological and biochemical evidence support the notion that CKAMP44 and TARP γ-8 can be contained in the same AMPAR complex.

Control of AMPA Receptor Activity by the Extracellular Loops of Auxiliary Proteins

“…Both these signatures of activity should be useful tools for investigating TARP action in synapses, including understanding the relative importance of assembly into complexes for anchoring (Opazo et al, 2010) as opposed to kinetic modulation, for clarifying the consequences of TARP modulation for short term plasticity (Devi et al, 2016), and for better identifying TARPs in ternary complexes with other auxiliary subunits (Khodosevich et al, 2014;Herring et al, 2013).…”

“…The physiological importance of modulation is likely to be the specialization of particular codes of short-term plasticity, in the hippocampus and cerebellum at least (von Engelhardt et al, 2010;Klaassen et al, 2016;Khodosevich et al, 2014;Devi et al, 2016). Recently, antagonists of AMPA receptors that target GluA2-g8 complexes were described (Maher et al, 2016;Kato et al, 2016), further enhancing interest in the molecular basis of complexes of GluA subunits and their auxiliary proteins as potential drug targets.…”

Modulation der Funktion von AMPA-Rezeptoren durch auxiliäre Proteine

“…So kann CKAMP44 auch an AMPA -Rezeptoren binden, an die gleichzeitig auch 4 TARPMoleküle binden. Interessanterweise binden zumindest ein Teil der AMPA -Rezeptoren in Körnerzellen des Hippocampus sowohl CKAMP44 als auch TARP γ-8 [ 5 ]. Biochemische Analysen zeigten, dass CKAMP44 mit den GluA1-, GluA2-und GluA3-Untereinheiten interagiert(die Interaktion mit GluA4 wurde bisher nicht untersucht) , aber nicht mit NMDA-oder Kainat -Rezeptoren.…”

“…Kürzlich haben wir gezeigt, dass CKAMP44 ebenfalls am C-Terminus ein PDZ-Domänen -Bindungsmotiv (EVTV) hat, über das es mit PSD95 interagiert. Deletion dieses Motivs führt zu einem kompletten Verlust des Einflusses auf die Zahl synaptischer AMPA -Rezeptoren, wogegen der Einfluss auf die Zahl extrasynaptischer Rezeptoren nicht beeinträchtigt wird [ 5 ]. Dies zeigt, dass CKAMP44 die Zahl der AMPA -Rezeptoren auf der Zellmembran ebenfalls in einem zweistufigen Prozess kontrolliert.…”

Facilitated c-Fos Induction in Mice Deficient for the AMPA Receptor-Associated Protein Ckamp44

“…We recently identified the Cystine-knot containing AMPAR-associated protein (Ckamp44 also called Shisa9) (Pei and Grishin 2012) as novel AMPAR-associated protein (Schwenk et al 2012;von Engelhardt et al 2010). In the absence of Ckamp44, the amplitude of AMPAR-mediated currents is reduced, their recovery from desensitization is much faster, and the short-term plasticity is impaired (Khodosevich et al 2014;von Engelhardt et al 2010). Therefore, altered AMPAR signalling of Ckamp44 -/-mice might also affect NMDAR signalling which is dependent on the AMPAR-mediated membrane depolarisation.…”