Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors

Abstract

The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind L-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2

Ethylene-independent signaling by the ethylene precursor ACC in Arabidopsis ovular pollen tube attraction

“…Although not synthesized in animal tissues, ACC is a partial agonist of ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels involved in electric and Ca 2+ signaling in neurons 29 – 31 . Given ACC’s signaling function in plants, we investigated whether ACC is capable of stimulating the plant homologs of iGluRs known as GLR channels.…”

Probing the ionotropic activity of glutamate GluD2 receptor in HEK cells with genetically-engineered photopharmacology

“…Other ligands such as D-serine and glycine bind to the LBD and reduce spontaneous currents in GluD2 Lc , which suggests a coupling between the LBD and the channel ( Naur et al, 2007 ; Hansen et al, 2009 ), but these molecules have broad spectrum activity. Finally, 7-chlorokynurenic acid has been identified to modulate GluD2 Lc current by binding to the D-serine site but it is also a GluN1 competitive antagonist ( Kristensen et al, 2016 ).…”

Ionotropic glutamate receptors (iGluRs) of the delta family (GluD1 and GluD2) and synaptogenesis

“…55 This modulation required the intact intracellular C-terminal domain (CTD) of GluD2, which interacts with a range of scaffolding and signaling proteins. 73 C-terminal portion of GluD2 consists of a PDZ binding motif, to which PDZ proteins, such as PSD-93, protein tyrosine phosphatase (PTPMEG), synaptic scaffolding molecule SSCAM, n-PIST, and delphilin can bind. 54 Furthermore, D-serine released from Bergmann glia can bind to the ligand binding domain of GluD2 and induce AMPA receptor endocytosis and LTD. 55 Similarly, application of an antibody against the Figure 2 Signaling pathway of GluD1 receptor in the pyramidal neurons in medial prefrontal cortex (mPFC) and hippocampus.…”