Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes

Abstract

Fast excitatory neurotransmission is mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptor (AMPAR). AMPARs initiate depolarization of the postsynaptic neuron by allowing cations to enter through their ion channel pores in response to binding of the neurotransmitter glutamate. AMPAR function is dramatically affected by auxiliary subunits, which are regulatory proteins that form various complexes with AMPARs throughout the brain. The most well-studied auxiliary subunits are the transmembrane AMPAR regulatory proteins (TARPs), which alter the assembly, trafficking, localization, kinetics, and pharmacology of AMPARs. Recent structural and functional studies of TARPs and the TARP-fold germ cell-specific gene 1-like (GSG1L) subunit have provided important glimpses into how auxiliary subunits regulate the function of synaptic complexes. In this review, we put these recent structures in the context of new functional findings in order to gain insight into the determinants of AMPAR regulation by TARPs. We thus reveal why TARPs display a broad range of effects despite their conserved modular architecture.

Hodgkin–Huxley–Katz Prize Lecture: Genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif

“…2019; Twomey et al . 2019; Wang & Furukawa, 2019; Burada et al . 2020), which also became templates for molecular modelling (Mollerud et al .…”

α2δ‐1 protein promotes synaptic expression of Ca2+ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension

“…Thus, α2δ-1 controls the assembly and composition of AMPARs independently of Ca 2+ channels. Notably, many γ subunits of calcium channels can alter the function and pharmacology of AMPARs, and they have now been termed as transmembrane AMPAR regulatory proteins (Twomey et al, 2019). Because of the unique role of α2δ-1 in regulating the assembly and composition of AMPARs, α2δ-1's function seems to be similar to transmembrane AMPAR regulatory proteins.…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…A substantial proportion of native AMPA receptors contain auxiliary subunits that include a surprisingly diverse range of structurally unrelated proteins (Jackson and Nicoll, 2011a;Straub and Tomita, 2012;Greger et al, 2017;Chen and Gouaux, 2019;Twomey et al, 2019;Kamalova and Nakagawa, 2021). AMPA receptor auxiliary subunits include TARPs (Chen et al, 2000;Tomita et al, 2003Tomita et al, , 2005aKato et al, 2008), cornichons (CNIHs) (Schwenk et al, 2009), cysteine-knot AMPA receptor modulating proteins (CKAMPS) (termed shisa proteins in the genome database) (von Engelhardt et al, 2010;Farrow et al, 2015), GSG1L (Schwenk et al, 2012;Shanks et al, 2012), and synapse differentiation-induced gene 4 (SynDIG4) [also known as proline rich transmembrane protein 1 (Prrt1)] (Matt et al, 2018) (Fig.…”