Kainate and AMPA receptors in epilepsy: Cell biology, signalling pathways and possible crosstalk

Henley, Jeremy M; Nair, Jithin; Seager, Richard; Yucel, Busra P.; Woodhall, Gavin L.; Henley, Benjamin S.; Talandyte, Karolina; Needs, Hope I; Wilkinson, Kevin A.

doi:10.1016/j.neuropharm.2021.108569

Cited by 20 publications

(13 citation statements)

References 215 publications

(246 reference statements)

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“…Kainate (KA) is an agonist of Kainate receptors (KARs), and also acts as a non-desensitizing agonist of AMPA receptors. KARs, ligand-gated channel ionic receptors, exist in the postsynaptic membrane and mediate a small portion of ionic synaptic responses, playing a key role in synaptic integration ( 90 ). KARs is a tetramer composed of five subunits, including GluK1-5, of which GluK2 subunit is a key determinant of KARs properties.…”

Section: Regulation Of Trp Metabolism On Downstream Targetsmentioning

confidence: 99%

Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

Long

et al. 2022

Front. Immunol.

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Neurological and psychiatric disorders are a category of chronic diseases that are widespread and pose serious mental and physical health problems for patients. The substrates, products, and enzymes of Tryptophan metabolism all contribute to the development of neurological and psychiatric disorders. This paper deals with three metabolic pathways of tryptophan that produce a series of metabolites called tryptophan Catabolics (TRYCATs). These metabolites are involved in pathological processes such as excitotoxicity, neuroinflammation, oxidative stress, and mitochondrial damage and are closely associated with neurological and psychiatric disorders such as Alzheimer’s disease and depression. Here, we review the elements that affect how tryptophan metabolism is regulated, including inflammation and stress, exercise, vitamins, minerals, diet and gut microbes, glucocorticoids, and aging, as well as the downstream regulatory effects of tryptophan metabolism, including the regulation of glutamate (Glu), immunity, G-protein coupled receptor 35 (Gpr35), nicotinic acetylcholine receptor (nAChR), aryl hydrocarbon receptor (AhR), and dopamine (DA). In order to advance the general understanding of tryptophan metabolism in neurological and psychiatric disorders, this paper also summarizes the current situation and effective drugs of tryptophan metabolism in the treatment of neurological and psychiatric disorders and considers its future research prospects.

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Section: Regulation Of Trp Metabolism On Downstream Targetsmentioning

confidence: 99%

Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

Long

et al. 2022

Front. Immunol.

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“…Kainate receptors are expressed in regions of spinal cord implied in the transmission of sensory stimulation and pain, and their functional dysregulation was linked to pain [ 38 , 39 ]. Several studies led to a variety of linkages between epilepsy and kainate receptors including different and sometimes contradictory mechanisms that clearly demonstrate the difficulty in studying kainate receptors in this respect [ 39 , 40 , 41 ].…”

Section: Willardiine and Its Analoguesmentioning

confidence: 99%

Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid

et al. 2022

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Willardiine is a nonprotein amino acid containing uracil, and thus classified as nucleobase amino acid or nucleoamino acid, that together with isowillardiine, forms the family of uracilylalanines isolated more than six decades ago in higher plants. Willardiine acts as a partial agonist of ionotropic glutamate receptors and more in particular it agonizes the non-N-methyl-D-aspartate (non-NMDA) receptors of L-glutamate: ie. the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate receptors. Several analogues and derivatives of willardiine have been synthesised in the laboratory in the last decades and these compounds show different binding affinities for the non-NMDA receptors. More in detail, the willardiine analogues have been employed not only in the investigation of the structure of AMPA and kainate receptors, but also to evaluate the effects of receptor activation in the various brain regions. Remarkably, there are a number of neurological diseases determined by alterations in glutamate signaling, and thus, ligands for AMPA and kainate receptors deserve attention as potential neurodrugs. In fact, similar to willardiine its analogues often act as agonists of AMPA and kainate receptors. A particular importance should be recognized to willardiine and its thymine-based analogue AlaT also in the peptide chemistry field. In fact, besides the naturally-occurring short nucleopeptides isolated from plant sources, there are different examples in which this class of nucleoamino acids was investigated for nucleopeptide development. The applications are various ranging from the realization of nucleopeptide/DNA chimeras for diagnostic applications, and nucleoamino acid derivatization of proteins for facilitating protein-nucleic acid interaction, to nucleopeptide-nucleopeptide molecular recognition for nanotechnological applications. All the above aspects on both chemistry and biotechnological applications of willardine/willardine-analogues and nucleopeptide will be reviewed in this work.

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“…The authors also highlight inconsistencies regarding the links between certain mutations in KAR subunitencoding genes and psychiatric disorders and stress the need for more detailed evaluation of the intrinsic properties of mutant receptors together with the underlying mechanisms in mouse models to develop a better understanding of pathological changes. Henley et al (2021) review the roles KARs and AMPARs play in the onset and maintenance of epilepsy through altered cell surface trafficking and signalling mechanisms. The authors focus on the mRNA editing, protein-protein interactions, post-translational modifications, and activity-induced cell surface expression of two key pore-forming subunits of KARs (GluK2) and AMPARs (GluA2) in the context of epilepsy.…”

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confidence: 99%

Kainate receptors in brain function and disorders

Molnár

2022

Neuropharmacology

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Kainate and AMPA receptors in epilepsy: Cell biology, signalling pathways and possible crosstalk

Cited by 20 publications

References 215 publications

Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders

Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid

Kainate receptors in brain function and disorders

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