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Last update 23 Jan 2025

GluK5

Last update 23 Jan 2025

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

LY-466195

Target

GluK5 x Kainate receptor

Mechanism

GluK5 antagonists [+1]

Active Org.

Eli Lilly & Co. [+1]

Originator Org.

Eli Lilly & Co.

Active Indication

Migraine Disorders

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

276

Literatures (Medical) associated with GluK5

01 Jan 2025·Proteins: Structure, Function, and Bioinformatics

Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor

Article

Author: Berka, Vladimir ; Paudyal, Nabina ; Carrillo, Elisa ; Das, Anindita ; Jayaraman, Vasanthi

AbstractKainate receptors are a subtype of ionotropic glutamate receptors that form transmembrane channels upon binding glutamate. Here, we have investigated the mechanism of partial agonism in heteromeric GluK2/K5 receptors, where the GluK2 and GluK5 subunits have distinct agonist binding profiles. Using single‐molecule Förster resonance energy transfer, we found that at the bi‐lobed agonist‐binding domain, the partial agonist AMPA‐bound receptor occupied intermediate cleft closure conformational states at the GluK2 cleft, compared to the more open cleft conformations in apo form and more closed cleft conformations in the full agonist glutamate‐bound form. In contrast, there is no significant difference in cleft closure states at the GluK5 agonist‐binding domain between the partial agonist AMPA‐ and full agonist glutamate‐bound states. Additionally, unlike the glutamate‐bound state, the dimer interface at the agonist‐binding domain is not decoupled in the AMPA‐bound state. Our findings suggest that partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation.

01 Dec 2024·Molecular Diversity

Synthesis of propargylamine: pioneering a green path with non-conventional KA2 coupling approach

Review

Author: Khadanga, Lambodar ; Roopan, Selvaraj Mohana

The KA² coupling reaction is a well-explored and versatile method for forming C-C bonds in synthetic chemistry. It is composed of ketone, amine, and alkyne, which play a major role in the synthesis of propargylamines, known for their diverse biological activities and are used in treating neurogenetical disorders. The KA² coupling is highly challenging due to the low reactivity of ketimines toward nucleophilic attacks with metal acetylide intermediates formed by activating the C-H bond of the alkyne. Despite predominant studies conducted on thermal conditions for KA² coupling reactions, green and sustainable approaches like non-conventional methods still have a lot to achieve. This review article provides a comprehensive introduction to the non-conventional approach in the KA² coupling reaction, outlining its mechanisms and exploring future aspects.

01 Dec 2024·Alzheimer's & Dementia

Loss of presenilin 2 function increases susceptibility to kainate‐induced status epilepticus and attenuates associated increases in hippocampal kainate‐type glutamate receptor expression

Article

Author: Barker‐Haliski, Melissa ; Koutoubi, Rami ; Robinson‐Cooper, Larissa ; Davidson, Stephanie

AbstractBackgroundPresenilin 2 (PSEN2) is one of three deterministic risk genes that increases the risk of early‐onset Alzheimer’s Disease. People with PSEN2 variants have increased risk of unprovoked seizures versus age‐matched unaffected individuals yet few studies have interrogated the contributions of PSEN2 on seizure susceptibility. Critically, PSEN proteolytic capacity may be a novel regulator of hippocampal kainate‐type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). We thus hypothesized PSEN2‐KO mice would demonstrate reduced KA‐SE latency, increased SE severity, worsened outcomes 7‐days later, and have altered hippocampal KAR expression versus similarly treated WT mice.MethodUsing a repeated low‐dose systemic KA administration model to evoke SE, we quantified the latency to SE and extent of SE‐induced neuropathology in 3–4‐month‐old male and female PSEN2‐KO versus WT mice (n = 10‐16 mice/group/sex). GluK5, a KAR subunit, expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA‐SE or sham to define the impacts of PSEN2 deletion and SE on hippocampal KAR expression.ResultRegardless of sex, PSEN2‐KO mice were more susceptible to KA‐SE than WT mice. Male PSEN2‐KO mice progressed to SE faster than WTs (78.6±25.3 versus 98.2±16.0 min; t = 2.43, p = 0.027); female PSEN2‐KO mice were also more susceptible to KA‐SE relative to WTs (85.3±32.2 versus 112.2±15.4 min; t = 2.45, p = 0.022). Basal GluK5 expression did not differ between sexes or genotypes. However, in male mice 7‐days post‐KA‐SE insult GluK5 expression was significantly increased over basal levels in WT mice (p = 0.0028), but PSEN2‐KO mice GluK5 levels were unchanged from basal expression (p = 0.9819). Regardless of genotype, female mice GluK5 levels were unchanged from basal expression at 7‐days post‐KA‐SE insult, revealing sex differences in post‐SE outcomes.ConclusionLoss of normal PSEN2 function increases susceptibility to KA‐induced seizures and SE, which cannot be explained by basal GluK5 expression differences. However, increased GluK5 expression in male WT relative to PSEN2‐KO mice 7‐days post KA‐SE, further substantiates a role of PSEN2 in KAR availability. Sex differences in GluK5 and GFAP were also apparent post‐SE.

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GluK5

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