Last update 19 Sep 2024

GluK5

Last update 19 Sep 2024

Basic Info

Synonyms

EAA2, Excitatory amino acid receptor 2, GluK5

+ [7]

Introduction

Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds kainate > quisqualate > domoate > L-glutamate >> AMPA >> NMDA = 1S,3R-ACPD.

Drugs associated with GluK5

NS3763

Target

GluK5

Mechanism

GluK5 antagonists

Active Org.

Neurosearch

Originator Org.

Neurosearch

Active Indication

Epilepsy [+2]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

LBG20304

Target

GluK5

Mechanism

GluK5 agonists

Active Org.

University of Copenhagen

Originator Org.

University of Copenhagen

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GluK5

100 Translational Medicine associated with GluK5

0 Patents (Medical) associated with GluK5

268

Literatures (Medical) associated with GluK5

22 Aug 2024·Journal of Medicinal Chemistry

Domoic Acid as a Lead for the Discovery of the First Selective Ligand for Kainate Receptor Subtype 5 (GluK5)

Article

Author: Buschbom-Helmke, Silke ; Wang, Pengfei ; Miguez-Cabello, Federico ; Bowie, Derek ; Bunch, Lennart ; Carta, Mario ; Pickering, Darryl S. ; Nielsen, Birgitte ; Jørgensen, Flemming Steen ; Mulle, Christophe ; Viotti, Julio S. ; Alcaide, Anna

Twenty-one simplified analogues of the natural product domoic acid were designed, synthesized, and then characterized at homomeric kainic acid (KA) receptors (GluK1-3,5). LBG20304 displays a high affinity for homomeric GluK5 receptors (IC₅₀ = 432 nM) with a >40-fold selectivity over homomeric GluK1-3 subtypes and ≫100-fold selectivity over native AMPA and N-methyl d-aspartate receptors. Functional studies of LBG20304 on heteromeric GluK2/5 receptors show no agonist or antagonist functional response at 10 μM, while a concentration of 100 μM at neuronal slices (rat) shows low agonist activity. A molecular dynamics simulation of LBG20304, in a homology model of GluK5, suggests specific interactions with the GluK5 receptor and an occluded ligand binding domain, which is translated to agonist or partial agonist activity. LBG20304 is a new compound for the study of the role and function of the KA receptors with the aim of understanding the involvement of these receptors in health and disease.

01 Oct 2023·Annals of neurology

GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy.

Article

Author: Mulle, Christophe ; Deforges, Severine ; Viotti, Julio ; Appay, Romain ; Khalilov, Ilgam ; Dougy, Etienne ; Marissal, Thomas ; Scavarda, Didier ; Peret, Angélique ; Villeneuve, Nathalie ; Giles, April ; Marchal, Cécile ; Maréchal, Marine ; Tong, Soutsakhone ; Boileau, Céline ; Figarella-Branger, Dominique ; Lepine, Anne ; Lagarde, Stanislas ; Bartolomei, Fabrice ; Smith, Jared B ; Danos, Olivier ; Martineau, Fanny ; Rumi, Julie ; Crépel, Valérie ; Baudouin, Stéphane ; Janowitz, Haley ; Gautron, Justine ; Khazipov, Roustem ; Partouche, Nicolas ; Mercer, Andrew ; Trebuchon, Agnès ; Porter, Richard ; Milh, Mathieu ; Penchet, Guillaume

OBJECTIVETemporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE.METHODSWe combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE.RESULTSHere, we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated interictal-like epileptiform discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs.INTERPRETATIONOur gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients. ANN NEUROL 2023;94:745-761.

01 Oct 2023·DNA and cell biology

Altered G-Protein Transduction Protein Gene Expression in the Testis of Infertile Patients with Nonobstructive Azoospermia.

Article

Author: Azizi, Hossein ; Skutella, Thomas ; Hashemi Karoii, Danial

Recent studies have shown that several members of the G-protein-coupled receptors (GPCR) superfamily play crucial roles in the maintenance of ion-water homeostasis of the sperm and Sertoli cells, development of the germ cells, formation of the blood barrier, and maturation of sperm. The GPCR, guanyl-nucleotide exchange factor, membrane traffic protein, and small GTPase genes were analyzed by microarray and bioinformatics (3513 sperm and Sertoli cell genes). In the microarray analyses of three human cases with different nonobstructive azoospermia sperm, the expression of GOLGA8IP, OR2AT4, PHKA1, A2M, OR56A1, SEMA3G, LRRC17, APP, ARHGAP33, RABGEF1, NPY2R, GHRHR, LTB4R2, GRIK5, OR6K6, NAPG, OR6C65, VPS35, FPR3, and ARL4A was upregulated, while expression of MARS, SIRPG, OGFR, GPR150, LRRK1, and NGEF was downregulated. There was an increase in GBP3, GBP3, TNF, TGFB3, and CLTC expression in the Sertoli cells of three human cases with NOA, whereas expression of PAQR4, RRAGD, RAC2, SERPINB8, IRPB1, MRGPRF, RASA2, SIRPG, RGS2, RAP2A, RAB2B, ARL17, SERINC4, XIAP, DENND4C, ANKRA2, CSTA, STX18, and SNAP23 were downregulated. A combined analysis of Enrich Shiny Gene Ontology (GO), STRING, and Cytoscape was used to predict proteins' molecular interactions and then to recognize master pathways. Functional enrichment analysis showed that the biological process (BP), regulation of protein metabolic process, regulation of small GTPase-mediated signal transduction were significantly expressed in up-/downregulated differentially expressed genes (DEGs) in sperm. In molecular function (MF) experiments of DEGs that were up-/downregulated, it was found that GPCR activity, guanyl ribonucleotide binding, GTPase activity and nucleoside-triphosphatase activity were overexpressed. An analysis of GO enrichment findings of Sertoli cells showed BP and MF to be common DEGs. When these gene mutations have been validated, they can be used to create new GPCR antagonists or agonists that are receptor-selective.

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