Abstract
AMPARs control fast synaptic communication between neurons and their function relies on auxiliary subunits, which importantly modulate channel properties. Although it has been suggested that AMPARs can bind to TARPs with variable stoichiometry, little is known about the effect that this stoichiometry exerts on certain AMPAR properties. Here we have found that AMPARs show a clear stoichiometry-dependent modulation by the prototypical TARP γ2 although the receptor still needs to be fully saturated with γ2 to show some typical TARP-induced characteristics (i.e. an increase in channel conductance). We also uncovered important differences in the stoichiometric modulation between calcium-permeable and calcium-impermeable AMPARs. Moreover, in heteromeric AMPARs, γ2 positioning in the complex is important to exert certain TARP-dependent features. Finally, by comparing data from recombinant receptors with endogenous AMPAR currents from mouse cerebellar granule cells, we have determined a likely presence of two γ2 molecules at somatic receptors in this cell type.
Highlights
Glutamate is a crucial neurotransmitter in the central nervous system (CNS), mediating the vast majority of the fast-excitatory synaptic transmission acting on postsynaptic ionotropic glutamate receptors
In order to study the effect of stoichiometry on heteromeric GluA2-containing CI-AMPARs, we focused on GluA2/GluA4, the putative AMPAR present in cerebellar granule cells (CGCs) (Mosbacher et al, 1994)
One of the first evidences of a functionally variable AMPAR-TARP stoichiometry came from the observation that mEPSCs were differentially altered depending on the TARP expression levels (Milstein et al, 2007)
Summary
Glutamate is a crucial neurotransmitter in the central nervous system (CNS), mediating the vast majority of the fast-excitatory synaptic transmission acting on postsynaptic ionotropic glutamate receptors. TARPs are one of the most studied AMPAR auxiliary proteins because of their indispensable role in neuronal physiology (see Payne, 2008 for review) and in different types of synaptic plasticity (Rouach et al, 2005; Louros et al, 2014; Sullivan et al, 2017; Louros et al, 2018) It is well-known that members of the TARP family can modify biophysical properties of AMPARs by increasing conductance, slowing down kinetics or diminishing polyamine block in CP-AMPARs (Straub and Tomita, 2012; Haering et al, 2014; Jackson and Nicoll, 2011; Greger et al, 2017). We propose that just 2 molecules of the TARP family ( g2) determine functional somatic AMPAR properties in CGCs acting in a complex manner on both GluA2 and GluA4c subunits
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