Mechanisms for clearance of released N-acetylaspartylglutamate in crayfish nerve fibers: Implications for axon–glia signaling

Urazaev, A. Kh.; Buttram, J.G; Deen, Jochem; Gafurov, Boris; Slusher, Barbara S.; Grossfeld, Robert M.; Lieberman, Edward M.

doi:10.1016/s0306-4522(01)00393-1

Cited by 20 publications

(24 citation statements)

References 24 publications

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“…Lieberman and colleagues (35) have shown that GCPII-mediated hydrolysis of NAAG is constitutively quiescent and is induced selectively by nerve stimulation. Using microdialysis, we have shown that GCPII inhibition does not affect basal glutamate but selectively decreases the rise in extracellular glutamate after a pathological insult, e.g., stroke (19).…”

Section: Discussionmentioning

confidence: 99%

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghadge

Slusher

Bodner

et al. 2003

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

115

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Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and Ϸ20% of these cases of familial ALS (FALS) are caused by mutations of copper͞zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.A myotrophic lateral sclerosis (ALS) is a progressive and fatal degeneration of motor neurons (MNs) in the spinal cord and cerebral cortex. About 10% of ALS cases are inherited in an autosomal dominant fashion, and Ϸ20% of these cases of familial ALS (FALS) are caused by a mutation in copper͞zinc superoxide dismutase type 1 (SOD1) (1). Mice and rats that carry mutant (MT) SOD1 as a transgene manifest a progressive MN degeneration similar to that in patients with ALS (2-4). Several lines of evidence suggest that glutamate excitotoxicity is a pathogenic mechanism in both sporadic .N-acetylaspartylglutamate (NAAG) is one of the most abundant peptides in the mammalian central and peripheral nervous system (14), is present in neuronal vesicles, is released from neurons in a calcium-dependent manner, and functions as a high-affinity agonist at the group II metabotropic glutamate receptor subtype 3 (mGluR3). Activation of mGluR3 by NAAG has been shown to inhibit glutamate release (15), increase release of transforming growth factor ␤ (TGF␤) from glial cells, and provide neuroprotection (16). NAAG is hydrolyzed to N-acetylaspartate and glutamate by glutamate carboxypeptidase II (GCPII) (EC 3.4.17.21; also termed N-acetylated-␣-linked acidic dipeptidase or NAALADase; ref. 17), an enzyme localized on the plasma membrane of glial cells with its catalytic region facing the synapse (18). Therefore, inhibition of GCPII would be expected to provide neuroprotection by means of both decreasing glutamate and increasing NAAG (19).We hypothesized that GCPII inhibition would protect MNs expressing MT SOD1 from cell death, as well as ameliorate the MN degeneration seen in FALS transgenic mouse. For in vitro studies, we used 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent and selective GCPII inhibitor (K i ϭ 0.2 nM; ref. 20) that has been shown to selectively reduce ischemic glutamate and provide neuroprotection in cell culture and animal models of ischemia (19), diabetic neuropathy (21), and drug abuse (22, 23). For the animal studies, we used a recently discovered thiol-based GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA) (24). Unlike 2-PMPA, 2-MPPA is o...

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Section: Discussionmentioning

confidence: 99%

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghadge

Slusher

Bodner

et al. 2003

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

115

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“…On the contrary, no effect was yielded by N-acetylaspartate, the other product of NAAG hydrolysis that had been shown not to alter glial potentials. Both NAAG and glutamate bind to class II metabotropic glutamate receptors, but only glutamate binds to the glial NMDA receptor (102,304). Hence, similar experiments were made with NMDA and D-aspartate, an additional NMDA receptor agonist that is present in the axoplasm of squid giant axons (65).…”

Section: The Squid Giant Axonmentioning

confidence: 93%

“…One such agent, the dipeptide N-acetylaspartylglutamate (NAAG) had been shown to be the first neurotransmitter released by stimulated crayfish axons (102,304). Addition of NAAG to the incubation medium also produced a dual wave of enhanced delivery of radiolabeled RNA to the axon perfusate, mimicking the effect of membrane depolarization (Fig.…”

Section: The Squid Giant Axonmentioning

confidence: 99%

Local Gene Expression in Axons and Nerve Endings: The Glia-Neuron Unit

Giuditta¹,

Chun²,

Eyman³

et al. 2008

Physiological Reviews

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Neurons have complex and often extensively elongated processes. This unique cell morphology raises the problem of how remote neuronal territories are replenished with proteins. For a long time, axonal and presynaptic proteins were thought to be exclusively synthesized in the cell body, which delivered them to peripheral sites by axoplasmic transport. Despite this early belief, protein has been shown to be synthesized in axons and nerve terminals, substantially alleviating the trophic burden of the perikaryon. This observation raised the question of the cellular origin of the peripheral RNAs involved in protein synthesis. The synthesis of these RNAs was initially attributed to the neuron soma almost by default. However, experimental data and theoretical considerations support the alternative view that axonal and presynaptic RNAs are also transcribed in the flanking glial cells and transferred to the axon domain of mature neurons. Altogether, these data suggest that axons and nerve terminals are served by a distinct gene expression system largely independent of the neuron cell body. Such a local system would allow the neuron periphery to respond promptly to environmental stimuli. This view has the theoretical merit of extending to axons and nerve terminals the marginalized concept of a glial supply of RNA (and protein) to the neuron cell body. Most long-term plastic changes requiring de novo gene expression occur in these domains, notably in presynaptic endings, despite their intrinsic lack of transcriptional capacity. This review enlightens novel perspectives on the biology and pathobiology of the neuron by critically reviewing these issues.

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“…To bring these NAAG peptidase inhibitors to the marketplace, it will be equally important to optimize their pharmacokinetic profiles [19]. As reported previously, this new approach to modulate glutamate levels via NAAG peptidase inhibition does not affect basal glutamate but selectively decreases the excitotoxic rise in extracellular glutamate following a pathological insult [42,84]. Several studies finding that GCPII knockout mice exhibit normal neurological function and behavior strengthen the potential of NAAG peptidase inhibition to serve as a therapeutic strategy, and this might act without the known side-effects associated with conventional glutamate receptor antagonists [37,60].…”

Section: Discussionmentioning

confidence: 88%

Blockade ofN-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders

Zhong

Luo

Jiang

2014

International Journal of Neuroscience

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The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.

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Mechanisms for clearance of released N-acetylaspartylglutamate in crayfish nerve fibers: Implications for axon–glia signaling

Cited by 20 publications

References 24 publications

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Local Gene Expression in Axons and Nerve Endings: The Glia-Neuron Unit

Blockade ofN-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders

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