Fig. 3: Domain architecture of GluD1 and current therapeutic strategies targeting its modular structure.
From: GluD1 at the synaptic crossroads: from domain structure to circuit dysfunction
The structural model of the GluD1 receptor delineates its four principal domains: the amino-terminal domain (ATD), ligand-binding domain (LBD), transmembrane domain (TMD), and carboxy-terminal domain (CTD). Each domain is associated with emerging pharmacological interventions or interacting ligands. At the extracellular ATD, cerebellin family proteins (Cbln1–4) bind to form transsynaptic scaffolds that are crucial for synapse formation and maintenance. Within the LBD, GluD1 interacts with ligands such as D-serine and GABA, which induce conformational changes that modulate synaptic plasticity through non-ionotropic mechanisms. The TMD, although structurally capable of forming a channel, exhibits latent ionotropic activity; gain-of-function mutants or engineered conditions reveal channel activity that can be inhibited by small-molecule blockers such as pentamidine and NASPM. The intracellular CTD contains essential motifs for trafficking and signaling; short synthetic peptides (e.g., Tat-HRSPN and Tat-SRTLS) derived from this region have demonstrated therapeutic efficacy in restoring synaptic function and reversing circuit-level plasticity in chronic pain models. This figure illustrates the therapeutic significance of targeting GluD1’s domain-specific interactions and downstream signaling cascades in neurological and neuropsychiatric disorders.
