N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease

Abstract

N-methyl-D-aspartate (NMDA) receptors are the major mediator of excitotoxicity. Although physiological activation of the NMDA receptor is necessary for cell survival, overactivation is a signal for cell death. Several pathways are activated through NMDA receptor stimulation, most of which can contribute to excitotoxicity. These include events leading to mitochondrial dysfunction, activation of calcium-dependent enzymes, and activation of mitogen-activated protein kinase pathways. Understanding the role of these mechanisms is important in developing agents that block excitotoxicity without inhibiting functions necessary for survival. NMDA receptor subtypes may be responsible for mediating separate pathways, and subtype-specific inhibition has shown promising results in some neurological models. This review examines the roles of NMDA receptor subtypes in excitotoxicity and neurological disorders.

Neuregulin1/ErbB4-induced migration in ST14A striatal progenitors: calcium-dependent mechanisms and modulation by NMDA receptor activation

“…NMDA at high concentrations can be cytotoxic, depending on receptor density and subunit composition [27]. NMDA could also increase cell proliferation and/or survival, as demonstrated by several groups by in vivo and in vitro experiments [28,29].…”

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

“…Among the different routes of calcium entry, NMDARs, a subtype of ionotropic glutamate receptors, are of particular interest because of their special ability to gate high levels of Ca 2 + infl ux (Rothman and Olney , 1995 ). Thus, these receptors have been extensively studied for their crucial role in synaptic plasticity and neuronal damage occurring during acute or chronic pathologies (Waxman and Lynch , 2005 ). Dennis Choi was the fi rst to demonstrate that the NMDARs were the primary source of toxic Ca 2 + infl ux mediating glutamate excitotoxicity (Choi et al , 1988 ).…”

“…Comparatively to other routes of Ca 2 + entry in neuronal cells, N -methyl-d -aspartate receptors (NMDARs), a subtype of ionotropic glutamate receptors, are of particular interest because of their special ability to gate high levels of Ca 2 + infl ux (Choi et al , 1988 ;Sattler et al , 1998 ). These receptors have been extensively studied for their crucial role in synaptic plasticity and excitotoxicity (Rothman and Olney , 1995 ;Waxman and Lynch , 2005 ). Moreover, excessive NMDAR activity was shown to contribute importantly to the etiology of many acute or chronic neurodegenerative disorders such as stroke, Hungtinton ' s disease, HIV-associated dementia and AD (Lipton and Rosenberg , 1994 ;Lancelot and Beal , 1998 ).…”

Chance favors the prepared mind

“…NMDAR hypofunction is hypothesized to result in the cognitive and behavioral abnormalities of schizophrenia, and direct antagonism of the NMDAR by drugs such as phencyclidine (PCP) and ketamine results in symptoms such as psychosis, hallucinations, delusions, agitation, and dissociative amnesia. [1][2][3][4] This constellation of symptoms is very similar to some of the initial neuropsychiatric symptoms observed in patients with anti-NMDAR encephalitis. Anti-NMDAR encephalitis was first described in 2005 as a paraneoplastic limbic encephalitis associated with ovarian teratoma.…”