title: 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.
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 (Ca(2+)) release, a main player in neuronal cell death in the central nervous system (CNS). However, CNS exposure to hypoxia modulates NMDAR/Ca(2+) physiology in such a way that there is a small window of operating neuroprotection, rather than the classical neuroinjurious effects manifested upon Ca(2+) 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.
authors.affiliation: Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon. john.haddad@yahoo.co.uk
authors.forename: John J
authors.initials: JJ
authors.lastname: Haddad
mesh_terms: D000818:Animals; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000378:metabolism*; D008958:Models, Molecular; D016202:N-Methylaspartate / Q000032:analysis / Q000378:metabolism*; D060066:Protein Interaction Maps; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate