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We investigated the mechanisms by which the antiparkinsonian and neuroprotective agents amantadine and memantine inhibit responses to N-methyl-D-aspartic acid (NMDA). Whole cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells expressing NMDA receptors. Both amantadine and memantine blocked NMDA-activated(More)
Transmitters mediating 'fast' synaptic processes in the vertebrate central nervous system are commonly placed in two separate categories that are believed to exhibit no interaction at the receptor level. The 'inhibitory transmitters' (such as glycine and GABA) are considered to act only on receptors mediating a chloride conductance increase, whereas(More)
N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels that are highly permeable to calcium and mediate activity-dependent synaptic plasticity. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain(More)
Oxidative stress can trigger neuronal cell death and has been implicated in several chronic neurological diseases and in acute neurological injury. Oxidative toxicity can be induced by glutamate treatment in cells that lack ionotrophic glutamate receptors, such as the immortalized HT22 hippocampal cell line and immature primary cortical neurons. Previously,(More)
Block of the channel of N-methyl-D-aspartate (NMDA) receptors by external Mg(2+) (Mg(o)(2+)) has broad implications for the many physiological and pathological processes that depend on NMDA receptor activation. An essential property of channel block by Mg(o)(2+) is its powerful voltage dependence. A widely cited explanation for the strength of the voltage(More)
The vital roles played by NMDA receptors in CNS physiology depend critically on powerful voltage-dependent channel block by external Mg(2+) (Mg(2+)(o)). NMDA receptor channel block by Mg(2+)(o) depends on receptor subunit composition: NR1/2A receptors (receptors composed of NR1 and NR2A subunits) and NR1/2B receptors are more strongly inhibited by Mg(2+)(o)(More)
Ionotropic glutamate receptor (iGluR) subunits contain a large N-terminal domain (NTD) that precedes the agonist-binding domain (ABD) and participates in subunit oligomerization. In NMDA receptors (NMDARs), the NTDs of NR2A and NR2B subunits also form binding sites for the endogenous inhibitor Zn(2+) ion. Although these allosteric sites have been(More)
N-methyl-D-aspartate receptors (NMDARs) mediate interneuronal communication and are broadly involved in nervous system physiology and pathology (Dingledine et al., 1999). Memantine, a drug that blocks the ion channel formed by NMDARs, is a widely prescribed treatment of Alzheimer's disease (Schmitt, 2005; Lipton, 2006; Parsons et al., 2007). Research on(More)
Memantine is a clinically useful drug in many neurological disorders, including Alzheimer's disease. The principal mechanism of action of memantine is believed to be the blockade of current flow through channels of N-methyl-d-aspartate (NMDA) receptors--a glutamate receptor subfamily broadly involved in brain function. Surprisingly, other drugs that block(More)
The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described(More)