Atypical Functional Properties of GluK3-Containing Kainate Receptors

Perrais, David; Coussen, Françoise; Mulle, Christophe

doi:10.1523/jneurosci.2724-09.2009

Cited by 40 publications

(63 citation statements)

References 51 publications

(111 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, the competitive antagonist UBP310 also exhibited a 17-fold higher K b value at the nondesensitizing GluK3 receptor (Table 3) compared to the K b value at wild-type GluK3 (Table 2). Finally, the wild-type GluK3 subtype has been shown to exhibit atypical function as compared to that of wild-type GluK1,2 (24).…”

Section: Resultsmentioning

confidence: 99%

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Larsen

Venskutonytė

Valadés

et al. 2010

ACS Chem. Neurosci.

View full text Add to dashboard Cite

The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Larsen

Venskutonytė

Valadés

et al. 2010

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Simulations of peak and equilibrium responses for the three kinetic models tested (see Fig. 8) were performed using rate constants published previously (Bowie et al, 1998;Zhang et al, 2008;Perrais et al, 2009). The software tool FACILE version 0.25 (courtesy of J. Ollivier, McGill University, Montreal, Canada) (Siso-Nadal et al, 2007) was used to convert the differential equations for each kinetic scheme into Matlab (version 7.8; MathWorks) format.…”

Section: Methodsmentioning

confidence: 99%

“…Altering closed-cleft stability reproduces the equilibrium/ peak response relationship To understand the source of this inverse relationship and the effect of cations on it, we performed kinetic simulations with two commonly used gating schemes of KARs, namely the single-open state model (Bowie et al, 1998) and a more recent multi-open state model (Perrais et al, 2009) of gating . We also included a third model that corresponds to a new type of gating scheme, the pregating model, recently assigned to AMPARs (Zhang et al, 2008).…”

Section: Cations Regulate the Equilibrium/peak Response Relationshipmentioning

confidence: 99%

Cations But Not Anions Regulate the Responsiveness of Kainate Receptors

MacLean

Wong²,

Fay³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

Kainate-selective ionotropic glutamate receptors are unique among ligand-gated ion channels in their obligate requirement of external anions and cations for activation. Although it is established that the degree of kainate receptor (KAR) activation is shaped by the chemical nature of the agonist molecule, the possible complementary role of external ions has yet to be examined. Here we show that external cations but not anions regulate the responsiveness to a range of full and partial agonists acting on rat GluK2 receptors. This observation is unexpected as previous work has assumed anions and cations affect KARs in an identical manner through functionally coupled binding sites. However, our data demonstrate that anion-and cation-binding pockets behave discretely. We suggest cations uniquely regulate a pregating or flipping step that impacts the closed-cleft stability of the agonist-binding domain (ABD). This model departs from a previous proposal that KAR agonist efficacy is governed by the degree of closure elicited in the ABD by ligand binding. Our findings are, however, in line with recent studies on Cys-loop ligand-gated ion channels suggesting that the "flipping" mechanism has been conserved by structurally diverse ligand-gated ion channel families as a common means of regulating neurotransmitter behavior.

show abstract

“…From recombinant studies, this subunit is known to exhibit highly distinctive pharmacological and biophysical properties (Porter et al 1997;Perrais et al 2009). In particular, it is activated only by very high concentrations of glutamate, and is readily desensitized.…”

Section: Kainate Receptor Interacting Proteins In the Cerebellummentioning

confidence: 99%

Glutamate Receptor Auxiliary Subunits and Interacting Protein Partners in the Cerebellum

Coombs

Cull-Candy

2013

Handbook of the Cerebellum and Cerebellar Disorders

View full text Add to dashboard Cite

AMPA-and kainate-type glutamate receptors play a central role in excitatory signaling and synaptic plasticity in the cerebellum. Considerable attention has therefore focused on the molecular mechanisms involved in the dynamic control of these receptors and their constituent subunits. A number of transmembrane and intracellular proteins have emerged as key molecular determinants of AMPA and kainate receptor behavior.Much of the early information on transmembrane AMPAR regulatory proteins (TARPs) arose from experiments on cerebellar neurons in stargazer mice. Although it is clear that the TARPs regulate AMPAR properties throughout the brain, the cerebellum continues to be a particularly suitable brain region for studies on the functional role of TARPs and many of the other receptorassociated proteins. This chapter focuses on the AMPA and kainate receptor subtypes and subunits present in the main cerebellar neurons and glia. In particular, we will consider recent evidence for the dynamic regulation of these receptor subunits by transmembrane and intracellular protein partners -in relation to cerebellar synaptic transmission and plasticity.

show abstract

Atypical Functional Properties of GluK3-Containing Kainate Receptors

Cited by 40 publications

References 51 publications

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Cations But Not Anions Regulate the Responsiveness of Kainate Receptors

Glutamate Receptor Auxiliary Subunits and Interacting Protein Partners in the Cerebellum

Contact Info

Product

Resources

About