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Ligand binding domain interface: A tipping point for pharmacological agents binding with GluN1/2A subunit containing NMDA receptors.
Bledsoe, Douglas; Vacca, Bryanna; Laube, Bodo; Klein, Bradley G; Costa, Blaise.
Afiliación
  • Bledsoe D; Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA, USA.
  • Vacca B; Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA, USA.
  • Laube B; Department of Neurophysiology and Neurosensory Systems, Technical University, Darmstadt, Germany.
  • Klein BG; Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA; School of Neuroscience, Virginia Tech, Blacksburg, VA, USA.
  • Costa B; Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA, USA; Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA; School of Neuroscience, Virginia Tech, Blacksburg, VA, USA. Electronic address: bcosta@vcom.vt.edu.
Eur J Pharmacol ; 844: 216-224, 2019 Feb 05.
Article en En | MEDLINE | ID: mdl-30553788
N-methyl D-aspartate (NMDA) receptors play a crucial role in normal brain function, pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDA receptor contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that evolve from six different genes including four GluN2 (A-D) and two GluN3 (A-B) subunits. Since NMDA receptors confer varied physiological properties and spatiotemporal distributions in the brain, pharmacological agents that target NMDA receptors with specific GluN2 subunits have significant potential for therapeutic applications. In the present work, by using electrophysiology techniques, we have studied the role of ligand binding domain (LBD) interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, channel blockers and an allosteric modulator. Remarkably, point mutations at the distal end (site-II&III) of GluN1 LBD interface increased memantine potency up to sevenfold when co-expressed with wild type GluN2A receptors but exhibit no effect on Mg2+ activity. Conversely, mutations at the proximal end (site-I) of the LBD interface did not affect the memantine but altered Zn2+ and Mg2+ potency towards opposite directions. These results indicate that GluN1/2A LBD interface interactions play a key role in determining channel function. Further, subtle changes in LBD interaction can be readily translated to the downstream extracellular vestibule of channel pore to adopt a conformation that may affect memantine, Zn2+ and Mg2+ binding. Further studies on NMDA receptor LBD to transmembrane domain signal propagation mechanisms will help develop GluN2 subunit selective biomolecules that can be used for the treatment of neurological and psychiatric disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de N-Metil-D-Aspartato / Subunidades de Proteína Idioma: En Revista: Eur J Pharmacol Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores de N-Metil-D-Aspartato / Subunidades de Proteína Idioma: En Revista: Eur J Pharmacol Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos