Write an assay on Regulation of central synapses by glutamate delta 1 receptor: Contribution to pain and gain.The glutamate delta 1 and delta 2 receptors form the delta subfamily of ionotropic glutamate receptors. GluD receptors are denoted to as “orphan” because of lack of a known ligand that can trigger channel opening in vitro.There are two subtypes of GluD: GluD1 and GluD2. These two receptors share 56% sequence homology. Expression of GluD2 is maximum in the cerebellum where it regulates motor function .GluD1, on the contrary, is enriched throughout the forebrain across myriad neuronal and synaptic subtypes and is implicated in behavioral plasticity and numerous higher-order functions including sociability, memory, and addiction. GluDs are unusual because they do not display typical agonist-induced currents like other iGluRs. Instead, GluDs are intricate in synapse formation and maintenance through interactions with presynaptic Neurexin and intermediary protein Cbln1. Together, the GluD-Cbln1-Neurexin forms a trans-synaptic complex that regulates synapse formation and maintenance. Glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachial-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ+) neurons, and their erasure may lead to aberrant social and emotional behavior because their deletion impairs excitatory neurotransmission at the PB-CeLC synapses. Structurally GluDs share many similarities to other iGluRs consisting of the amino-terminal domain, ligand binding domain and transmembrane domain. However, the ATD-LBD are arranged in a non-swapped conformation unlike other iGluRs. There are also differences in the C-terminal domain function of GluD1 related to receptor trafficking and LTP.
The GluD LBD crystal structure bears similarity to the GluN1 LBD and has a pocket where smaller amino acids including D-serine, glycine and others can bind. Binding of D-serine to the GluD2 LBD has been found to induce LTD at PF-PC synapses in early development, and this binding is also important for inhibitory synapse formation and generation of metabotropic currents. The central role of the LBD dimer interface in gating was documented in early studies where dimer-stabilizing mutations were found to attenuate AMPAR desensitization. Further, comparisons with the crystal structure of GluD2 ligand binding domain in complex with 7-chlorokynurenic acid (7-CKA) underlined evident differences in the ligand binding domain cleft closure. D-serine bound GluD2 ligand-binding domain shows closed cleft conformation. In contrast, the 7-CKA-bound ligand binding domain espoused open cleft conformation, as seen in apo (unbound) ligand-binding domain, although with different degrees of cleft opening. Remarkably, out of all the crystal structures of GluD2 ligand binding domain, an apo form containing calcium in the crystallization buffer crystallized as a dimer, similar to that in other ionotropic glutamate receptors.
