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Current Molecular Pharmacology
ISSN (Print): 1874-4672
ISSN (Online): 1874-4702
VOLUME: 6
ISSUE: 2
DOI: 10.2174/18744672113069990029      Price:  $58









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

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Author(s): John J. Haddad
Pages 104-135 (32)
Abstract:
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.
Affiliation:
Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon.