N-methyl-d-aspartate receptor function in neuronal and synaptic development and signaling

Pagano, Jessica; Giona, Federica; Beretta, Stefania; Verpelli, Chiara; Sala, Carlo

doi:10.1016/j.coph.2020.12.006

Cited by 31 publications

(21 citation statements)

References 54 publications

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“…The iGluRs have been divided into four subfamilies: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, kainate receptors, N-methyl-daspartate (NMDA) receptors and delta receptors (Traynelis et al 2010). AMPA receptors are considered as the primary mediators of fast neurotransmission, whereas NMDA receptors are detectors of glutamate release and postsynaptic depolarization leading to the induction of long-term synaptic changes (Pagano et al 2021). Kainate receptors are also widely expressed in the CNS, where they function as important regulators of both presynaptic and postsynaptic actions of glutamate (Contractor et al 2011).…”

Section: Introductionmentioning

confidence: 99%

“…AMPA receptors are considered as the primary mediators of fast neurotransmission, whereas NMDA receptors are detectors of glutamate release and postsynaptic depolarization leading to the induction of long‐term synaptic changes (Pagano et al . 2021). Kainate receptors are also widely expressed in the CNS, where they function as important regulators of both presynaptic and postsynaptic actions of glutamate (Contractor et al .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for positive allosteric modulation of AMPA and kainate receptors

Frydenvang

Pickering

Kastrup

2021

The Journal of Physiology

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This paper summarizes the present knowledge on how positive allosteric modulators (PAMs) interact with the ligand‐binding domain (LBD) of AMPA and kainate receptors, based on structure determinations. AMPA and kainate receptors belong to the family of ionotropic glutamate receptors that are responsible for mediating the majority of fast excitatory neurotransmission. These receptors have been related to brain disorders, e.g. Alzheimer's disease and attention deficit hyperactivity disorder. PAMs are small molecules that potentiate AMPA and kainate receptor currents by interfering with receptor desensitization. Therefore, PAMs are considered to be of interest for the development of pharmacological tools. Whereas PAMs for AMPA receptors have been known for several years, only recently have PAMs for kainate receptors been reported. Today, >80 structures are available for AMPA receptors with PAMs. These PAMs bind at the interface between two LBD subunits in the vicinity of residue 775, which is important for functional differences between flip and flop isoforms of AMPA receptors. PAMs can be divided into five classes based on their binding mode. The most potent PAM reported to date belongs to class 3, which comprises dimerized PAMs. Three structures of the kainate receptor GluK1 were determined with PAMs belonging to class 2. One PAM enhances kainate receptor currents 5‐ to 59‐fold but shows 100‐fold lower potency compared to AMPA receptors. Selective PAMs for kainate receptors will be of great use as pharmacological tools for functional investigations in vivo and might potentially prove useful as drugs in controlling the activity of neuronal networks.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural basis for positive allosteric modulation of AMPA and kainate receptors

Frydenvang

Pickering

Kastrup

2021

The Journal of Physiology

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“…The glutamatergic system of the central nervous system (CNS) is known to play a key role in memory consolidation and neurodegenerative processes leading to impairment of cognitive functions and memory during such diseases as AD and senile dementia [ 24 ]. Ionotropic glutamate receptors coupled to ion channels, in particular NMDA-subtype glutamate receptors, play an important role in these processes [ 25 , 26 , 27 ]. Compounds that are able to block NMDA receptors have long been considered as potential treatments for neurodegenerative diseases [ 28 , 29 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

et al. 2021

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A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biological activity. The synthesized conjugates showed new properties compared to their prototypes (memantine and dimebon), including the ability to bind to the ifenprodil-binding site of the NMDA receptor and to occupy the peripheral anionic site of acetylcholinesterase (AChE), which indicates that these compounds can act as blockers of AChE-induced β-amyloid aggregation. These new attributes of the conjugates represent improvements to the pharmacological profiles of the separate components by conferring the potential to act as neuroprotectants and cognition enhancers with a multifunctional mode of action.

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“…At the spinal cord level, they control fast sensory transmission and plasticity but also the generation of long-term memory in the cerebral cortex. They are differentiated into NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate (KA) receptors permeable to Na + or to Ca 2+ [ 107 ]. Glutamate is the major neurotransmitter between primary afferent fibers and dorsal horn neurons in the spinal cord and contributes to the genesis of excitatory postsynaptic currents (EPSCs) that play a role in pain and itch transmission via AMPA, KA and NMDA receptors [ 108 ].…”

Section: Ion Channels and Painmentioning

confidence: 99%

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

Diochot

2021

J. Venom. Anim. Toxins incl. Trop. Dis

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Pain is a common symptom induced during envenomation by spiders and scorpions. Toxins isolated from their venom have become essential tools for studying the functioning and physiopathological role of ion channels, as they modulate their activity. In particular, toxins that induce pain relief effects can serve as a molecular basis for the development of future analgesics in humans. This review provides a summary of the different scorpion and spider toxins that directly interact with pain-related ion channels, with inhibitory or stimulatory effects. Some of these toxins were shown to affect pain modalities in different animal models providing information on the role played by these channels in the pain process. The close interaction of certain gating-modifier toxins with membrane phospholipids close to ion channels is examined along with molecular approaches to improve selectivity, affinity or bioavailability in vivo for therapeutic purposes.

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N-methyl-d-aspartate receptor function in neuronal and synaptic development and signaling

Cited by 31 publications

References 54 publications

Structural basis for positive allosteric modulation of AMPA and kainate receptors

Structural basis for positive allosteric modulation of AMPA and kainate receptors

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

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