The Bioanalytical Molecular Pharmacology of the N-methyl-D-Aspartate (NMDA) Receptor Nexus and the Oxygen-Responsive Transcription Factor HIF-1α : Putative Mechanisms and Regulatory Pathways Unravel the Intimate Hypoxia Connection

Author(s): John J. Haddad

Journal Name: Current Molecular Pharmacology

Volume 6 , Issue 2 , 2013

Become EABM
Become Reviewer
Call for Editor


Hypoxia-mediated regulation of N-methyl-D-aspartate (NMDA) receptor (NMDAR) is phenomenal. NMDAR is no doubt an intriguing paradoxical glutamate receptor (GluR) with versatile actions. GluRs play a pivotal role in brain physiology and pathophysiology under ischemia and oxygen deprivation, where NMDARs are major contributors. Activation of NMDARs is closely associated with the kinetics of intracellular calcium (Ca2+) release, a main player in neuronal cell death in the central nervous system (CNS). However, CNS exposure to hypoxia modulates NMDAR/Ca2+ physiology in such a way that there is a small window of operating neuroprotection, rather than the classical neuroinjurious effects manifested upon Ca2+ release. The NMDAR connection with hypoxia-inducible factor-1α (HIF-1α), a transcription factor considered master regulator of oxygen sensing mechanisms, is not well established in the CNS. However, scanning the literature yielded a wealth of NMDAR/hypoxia connection but that with HIF-1α is not prominent. It is worth mentioning that this is not a comprehensive review on the effect of hypoxia on NMDAR physiology, rather this synopsis sheds light on the putative mechanisms involving HIF-1α and NMDAR regulation. Understanding the evidence of this intimate connection and its ramifications may bear potential applications in unraveling hypoxia-mediated injury, neuronal cell death and, most importantly, adaptive, neuroprotective mechanisms to oxygen deprivation.

Keywords: Apoptosis, anti-Inflammatory, antioxidants, cell death, central nervous system, glutamate, hypoxia-inducible factor, NMDA, neuroprotection.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2013
Published on: 30 June, 2013
Page: [104 - 135]
Pages: 32
DOI: 10.2174/18744672113069990029
Price: $65

Article Metrics

PDF: 27