A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

Abstract Precisely controlled synaptic glutamate concentration is essential for the normal function of the N‐methyl D‐aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psych...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Blaise M. Costa, Lina Cortés Kwapisz, Brittney Mehrkens, Douglas N. Bledsoe, Bryanna N. Vacca, Tullia V. Johnston, Rehan Razzaq, Dhanasekaran Manickam, Bradley G. Klein
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	anti‐NMDA receptor encephalopathy biased allosteric modulator (BAM) NMDA receptor schizophrenia Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/af4e8464cbf4484c997b749172315022
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:af4e8464cbf4484c997b749172315022
record_format	dspace
spelling	oai:doaj.org-article:af4e8464cbf4484c997b7491723150222021-11-16T13:45:55ZA glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons2052-170710.1002/prp2.859https://doaj.org/article/af4e8464cbf4484c997b7491723150222021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.859https://doaj.org/toc/2052-1707Abstract Precisely controlled synaptic glutamate concentration is essential for the normal function of the N‐methyl D‐aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration‐dependent NMDA receptor modulators would be clinically useful agents with fewer on‐target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage‐dependent effect. Patch‐clamp electrophysiology recordings confirmed agonist concentration‐dependent changes in maximum inducible currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration‐biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug‐like compounds for the treatment of treatment‐resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission.Blaise M. CostaLina Cortés KwapiszBrittney MehrkensDouglas N. BledsoeBryanna N. VaccaTullia V. JohnstonRehan RazzaqDhanasekaran ManickamBradley G. KleinWileyarticleanti‐NMDA receptor encephalopathybiased allosteric modulator (BAM)NMDA receptorschizophreniaTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	anti‐NMDA receptor encephalopathy biased allosteric modulator (BAM) NMDA receptor schizophrenia Therapeutics. Pharmacology RM1-950
spellingShingle	anti‐NMDA receptor encephalopathy biased allosteric modulator (BAM) NMDA receptor schizophrenia Therapeutics. Pharmacology RM1-950 Blaise M. Costa Lina Cortés Kwapisz Brittney Mehrkens Douglas N. Bledsoe Bryanna N. Vacca Tullia V. Johnston Rehan Razzaq Dhanasekaran Manickam Bradley G. Klein A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons
description	Abstract Precisely controlled synaptic glutamate concentration is essential for the normal function of the N‐methyl D‐aspartate (NMDA) receptors. Atypical fluctuations in synaptic glutamate homeostasis lead to aberrant NMDA receptor activity that results in the pathogenesis of neurological and psychiatric disorders. Therefore, glutamate concentration‐dependent NMDA receptor modulators would be clinically useful agents with fewer on‐target adverse effects. In the present study, we have characterized a novel compound (CNS4) that potentiates NMDA receptor currents based on glutamate concentration. This compound alters glutamate potency and exhibits no voltage‐dependent effect. Patch‐clamp electrophysiology recordings confirmed agonist concentration‐dependent changes in maximum inducible currents. Dynamic Ca2+ and Na+ imaging assays using rat brain cortical, striatal and cerebellar neurons revealed CNS4 potentiated ion influx through native NMDA receptor activity. Overall, CNS4 is novel in chemical structure, mechanism of action and agonist concentration‐biased allosteric modulatory effect. This compound or its future analogs will serve as useful candidates to develop drug‐like compounds for the treatment of treatment‐resistant schizophrenia and major depression disorders associated with hypoglutamatergic neurotransmission.
format	article
author	Blaise M. Costa Lina Cortés Kwapisz Brittney Mehrkens Douglas N. Bledsoe Bryanna N. Vacca Tullia V. Johnston Rehan Razzaq Dhanasekaran Manickam Bradley G. Klein
author_facet	Blaise M. Costa Lina Cortés Kwapisz Brittney Mehrkens Douglas N. Bledsoe Bryanna N. Vacca Tullia V. Johnston Rehan Razzaq Dhanasekaran Manickam Bradley G. Klein
author_sort	Blaise M. Costa
title	A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons
title_short	A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons
title_full	A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons
title_fullStr	A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons
title_full_unstemmed	A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons
title_sort	glutamate concentration‐biased allosteric modulator potentiates nmda‐induced ion influx in neurons
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/af4e8464cbf4484c997b749172315022
work_keys_str_mv	AT blaisemcosta aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT linacorteskwapisz aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT brittneymehrkens aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT douglasnbledsoe aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT bryannanvacca aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT tulliavjohnston aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT rehanrazzaq aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT dhanasekaranmanickam aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT bradleygklein aglutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT blaisemcosta glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT linacorteskwapisz glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT brittneymehrkens glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT douglasnbledsoe glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT bryannanvacca glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT tulliavjohnston glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT rehanrazzaq glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT dhanasekaranmanickam glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons AT bradleygklein glutamateconcentrationbiasedallostericmodulatorpotentiatesnmdainducedioninfluxinneurons
_version_	1718426498454519808

A glutamate concentration‐biased allosteric modulator potentiates NMDA‐induced ion influx in neurons

Ejemplares similares