GARLH Family Proteins Stabilize GABAA Receptors at Synapses

Abstract

Summary Ionotropic neurotransmitter receptors mediate fast synaptic transmission by functioning as ligand-gated ion channels. Fast inhibitory transmission in the brain is mediated mostly by ionotropic GABAA receptors (GABAARs), but their essential components for synaptic localization remain unknown. Here, we identify putative auxiliary subunits of GABAARs, which we term GARLHs, consisting of LH4 and LH3 proteins. LH4 forms a stable tripartite complex with GABAARs and neuroligin-2 in the brain. Moreover, LH4 is required for the synaptic localization of GABAARs and inhibitory synaptic transmission in the hippocampus. Our findings propose GARLHs as the first identified auxiliary subunits for anion channels. These findings provide new insights into the regulation of inhibitory transmission and the molecular constituents of native anion channels in vivo.

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

“…Similarly, over-expression of NL2 promotes GABAergic transmission and increases inhibitory synapse density (Chih et al, 2005; Chubykin et al, 2007). In addition, NL2, through the interaction with GARLHs, is important for synaptic localization of GABA A Rs, indicating a role of NL2 in functional maturation of GABAergic synapses (Yamasaki et al, 2017). However, loss-of-function studies have yielded different, often contradictory, conclusions.…”

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…In cerebellar Purkinje cells, Nlgn2 deletions caused decrease in inhibitory inputs that was greatly augmented by simultaneous deletion of Nlgn3 , which in itself had little effect (see below). Intracellularly, Nlgn2 binds to the inhibitory-synapse-specific molecules gephyrin, collibystin, GARLH3, and GARLH4, which may recruite Nlgn2 to synapses (Poulopoulos et al, 2009; Yamasaki et al, 2017). However, these interactions also appear to apply to other neuroligins, and at present it is unclear how Nlgn2 function is targeted to particular types of inhibitory synapses.…”

A tale of ligands big and small: An update on how pentameric ligand-gated ion channels interact with agonists and proteins

“…However, no bona fide auxiliary subunits were known for pLGICs until the recent discovery of the GARLH ( G ABA A R egulatory Lh fpl)-type transmembrane proteins. GARLHs control GABA A R synaptic localisation and GABA-mediated synaptic transmission by anchoring γ2-containing GABA A Rs to synaptic neuroligin-2 (NL-2), another synaptic transmembrane protein [66]. Specifically, the authors propose that GARLH4 forms a trimeric complex with (γ2-containing) GABA A Rs and NL-2.…”