8.A.16.5.3
Germ cell-specific gene-1-like (GSG1L) protein of 331 aas and 4 TMS in a 1 (N-terminal) + 3 TMS arrangement.  Calcium-permeable AMPA receptors (TC# 1.A.10) are specific for the neurotransmitter glutamate. They contribute to various forms of synaptic plasticity. Alterations in their expression or regulation are seen in a number of neurological conditions including stroke, motor neuron disease, and cocaine addiction. Several groups of auxiliary transmembrane proteins have been described that enhance the function and cell-surface expression of AMPARs, but GSG1L decreases channel conductance and calcium permeability while increasing polyamine-dependent rectification by diminishing outward current (McGee et al. 2015). GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by large structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry. AMPAR auxiliary subunits probably share a modular architecture (Twomey et al. 2017). It may also be a subunit of AMPA receptors (Matthews et al. 2021). Alternative splicing of the flip/flop cassette and TARP auxiliary subunits engage in a privileged relationship that fine-tunes AMPA receptor gating (Perozzo et al. 2023). Inclusion of the spider toxin analogue 1‑naphthylacetyl spermine (NASPM) in the intracellular solution results in complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, completely blocks outward synaptic currents. Thus, Coombs et al. 2023 identified a functional measure of CP-AMPARs that is unaffected by their auxiliary subunit content. Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that profoundly regulate glutamatergic synapse strength and plasticity (Perozzo et al. 2023).