NMDA receptors: from genes to channels

Sucher, Nikolaus J.; Awobuluyi, Marc; Choi, Yun-Beom; Lipton, Stuart A.

doi:10.1016/s0165-6147(96)80008-3

Cited by 251 publications

(28 citation statements)

References 62 publications

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“…It is also possible that synaptic changes in the other NMDA receptor subunit levels, such as NR2A and NR2B, might also be contributing to the enhancements in NMDA-mediated receptor LTP (19,20), as well as increased Ca 2ϩ influx through NMDA receptors (21). Studies have shown that recombinantly expressed heteromeric NR1-NR2 subunit receptors have distinct subunit-dependent biophysical and physiological properties that vary, depending on their stoichiometry, in the strength of the Mg 2ϩ block, sensitivity to modulation by glycine-reducing agents, and phosphorylation, desensitization, and offset decay kinetics, as well as affinities for antagonists and agonists (64). Future studies need to be directed towards examining the synaptic distribution of other NMDA receptor subunits after estrogen manipulation in young and aged animals.…”

Section: Discussionmentioning

confidence: 99%

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Adams

Shah

Janssen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

207

155

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Estrogen regulates hippocampal dendritic spine density and synapse number in an N-methyl-D-aspartate (NMDA) receptor-dependent manner, and these effects may be of particular importance in the context of age-related changes in endocrine status. We investigated estrogen's effects on axospinous synapse density and the synaptic distribution of the NMDA receptor subunit, NR1, within the context of aging. Although estrogen induced an increase in axospinous synapse density in young animals, it did not alter the synaptic representation of NR1, in that the amount of NR1 per synapse was equivalent across groups. Estrogen replacement in aged female rats failed to increase axospinous synapse density; however, estrogen up-regulated synaptic NR1 compared with aged animals with no estrogen. Therefore, the young and aged hippocampi react differently to estrogen replacement, with the aged animals unable to mount a plasticity response generating additional synapses, yet responsive to estrogen with respect to additional NMDA receptor content per synapse. These findings have important implications for estrogen replacement therapy in the context of aging.A t the turn of the century, the life expectancy of American women was roughly equivalent to the average age of the onset of menopause (1). Presently, there is a 30-year discrepancy between these two demographic indices, with a life expectancy of Ϸ80 years and the average onset of menopause remaining in the early fifties (1). As such, it is critical that we understand the interaction of reproductive senescence with the aging of other systems, particularly the nervous system. The regulation of the reproductive axis by estrogens has been characterized in great detail (2). However, estrogens also impact synaptic communication in brain regions involved in cognitive processing, such as the hippocampus (3), and these effects may be of particular importance in the context of aging when both circulating estrogen levels change and hippocampal-dependent functions decline. With respect to its nonreproductive functions, estrogen improves verbal memory and the capacity for learning new associations in both naturally and surgically menopausal women (4). In rats, although findings are somewhat controversial (5-7), learning was enhanced during the proestrus phase (i.e., high estrogen) of the estrous cycle compared with the estrus phrase (i.e., low estrogen) (8). Another study found improved learning and memory on the Morris water maze task in ovariectomized animals with intrahippocampal estrogen injection compared with saline injection (9).Our current understanding of estrogen effects on synaptic plasticity in the hippocampus is based almost exclusively on data from young animals. For example, dendritic spine density in CA1 pyramidal cells is sensitive to naturally occurring estrogen fluctuations in young animals (10), as well as experimentally induced estrogen depletion and replacement (11)(12)(13)(14). Recent evidence suggests that estrogens mediate these morphological changes through N-methyl-D-...

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Section: Discussionmentioning

confidence: 99%

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Adams

Shah

Janssen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

207

155

View full text Add to dashboard Cite

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“…In the CA1 region of the hippocampus, activation of these receptors is known to be required for induction of long term potentiation (LTP), a cellular process proposed by many as a possible mechanism of memory formation. Aberrant NMDA receptor function can result in cell death and may have implications in pathophysiologic disorders such as Parkinson's disease and epilepsy as well as age-related dementias like Alzheimer's disease (7)(8)(9)(10)(11). NMDA receptors are heteromeric assemblies of NR1 and NR2 subunits.…”

Section: Nmdamentioning

confidence: 99%

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

Alvestad¹,

Grosshans²,

Coultrap³

et al. 2003

Journal of Biological Chemistry

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NMDA1 receptors are ionotropic glutamate receptors that mediate calcium and sodium entry into neurons. In the CA1 region of the hippocampus, activation of these receptors is known to be required for induction of long term potentiation (LTP), a cellular process proposed by many as a possible mechanism of memory formation. Aberrant NMDA receptor function can result in cell death and may have implications in pathophysiologic disorders such as Parkinson's disease and epilepsy as well as age-related dementias like Alzheimer's disease (7-11). NMDA receptors are heteromeric assemblies of NR1 and NR2 subunits. The NR1 family is composed of a single gene, which can be alternatively spliced to generate eight theoretical splice variants (12). The NR2 family includes four genes, each encoding a unique subunit: NR2A, NR2B, NR2C, and NR2D (13). A third gene family, NR3, has been discovered, but the function of these subunits is not well understood. Whereas the NR1 subunit is required for a functional channel, differential incorporation of NR2 subunits regulates receptor function. The NR2 subunits, particularly NR2A and NR2B, have been shown to influence the sensitivity of NMDA receptors to ethanol block in cultured neurons as wells as transfected HEK293 cells and oocytes (14 -17). More recent studies have indicated that NR1 subunits may also play a key role in mediating the effects of ethanol on channel activity (18 -20).Ethanol is known to have widespread effects on the central nervous system. Ethanol inhibits transmission at the NMDAR subtype of glutamatergic excitatory synapses and enhances inhibitory GABAergic synaptic transmission. In addition, we and others have demonstrated that ethanol blocks LTP in the hippocampus (6,(21)(22)(23). Given that NMDA receptors are both required for induction of LTP and inhibited by ethanol, it is likely that inhibition of LTP by ethanol in the hippocampus is due, at least in part, to inhibition of NMDA receptors. The molecular mechanisms of this inhibition however, remain unknown.One hypothesis that we favor is that ethanol may inhibit the NMDAR by reducing its phosphorylation. Indeed, ethanol has been shown to enhance protein-tyrosine phosphatase activity and also inhibit receptor tyrosine kinase activity (24, 25). Moreover, previous studies suggest that Fyn, a member of the Src family of tyrosine kinases, may be a key player in regulating the sensitivity of NMDARs to ethanol in the hippocampus (26 -28

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“…The NMDA-Rs are hetero-oligomeric ligand-gated ion channels composed of a single NR1 subunit and one type of NR2 (A-D) subunit (6). The most abundant receptor subunits in the striatum are NR1, NR2A, and NR2B (7,8).…”

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confidence: 99%

Fyn Is Required for Haloperidol-induced Catalepsy in Mice

Hattori

Uchino

Isosaka

et al. 2006

Journal of Biological Chemistry

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Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidolinduced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D 2 receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyndeficient mice. Dopamine D 2 receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyndeficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D 2 receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response.Typical antipsychotic agents, such as haloperidol and chlorpromazine, have extrapyramidal side effects (EPS) 2 that resemble Parkinson disease. Drug-induced catalepsy, the impairment of movement initiation, in rodents is an animal model of EPS and is mainly caused by blockade of the dopamine D 2 receptor (D 2 -R) (1, 2).Haloperidol-induced responses are also dependent on N-methyl-Daspartate receptor (NMDA-R) activity, because prior administration of the NMDA-R antagonist MK-801 attenuates haloperidol-induced catalepsy (3, 4). D 2 -R and NMDA-R are co-expressed in close proximity along the dendrites of medium spiny neurons in the striatum, and they are functionally coupled in terms of controlling extrapyramidal functions (5).The NMDA-Rs are hetero-oligomeric ligand-gated ion channels composed of a single NR1 subunit and one type of NR2 (A-D) subunit (6). The most abundant receptor subunits in the striatum are NR1, NR2A, and NR2B (7, 8). These three subunits are involved in extrapyramidal functions (5), and we have found that an NR2B-selective antagonist attenuates haloperidol-induced catalepsy (9).Phosphorylation of tyrosine residues on the NMDA-R has been reported to modulate its channel characteristics (10, 11). Depriving the striatum of dopaminergic input increases the tyrosine phosphorylation of the striatal NMDA-R and the motor response (12, 13), but infusing the striatum with a tyrosine kinase inhibitor, genistein, attenuates both the tyrosine phosphorylation and the motor response induced by dopaminergic deprivation (13).Fyn is a member of the Src family kinases (SFKs) and is associated with the NMDA-R at postsynaptic d...

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NMDA receptors: from genes to channels

Cited by 251 publications

References 62 publications

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Tyrosine Dephosphorylation and Ethanol Inhibition of N-Methyl-d-aspartate Receptor Function

Fyn Is Required for Haloperidol-induced Catalepsy in Mice

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