Accumulation of amantadine by isolated chromaffin granules

Johnson, Robert G.; Carty, Sally E.; Scarpa, Antonio

doi:10.1016/0006-2952(81)90163-5

Cited by 15 publications

(11 citation statements)

References 22 publications

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“…Addition of bafilomycin A 1 to our synaptic vesicle preparation completely blocked glutamate uptake (data not shown). We also tested a high chloride medium (80 mM), which is known to increase the proton gradient across the vesicles and to facilitate the uptake of other transmitters such as acetylcholine and biogenic amines (34,35). D-Serine uptake into synaptic vesicles was also undetectable at a high chloride concentration (Fig.…”

Section: D-serine Synthesis and Serine Racemase In Neurons-mentioning

confidence: 99%

Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors

Kartvelishvily

Shleper

Balan

et al. 2006

Journal of Biological Chemistry

257

269

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The N-methyl-D-aspartate (NMDA) 2 type of glutamate receptor plays prominent roles in excitatory neurotransmission (1). In addition to glutamate, the NMDA receptor requires the obligatory binding of a coagonist of the NR1 subunit to mediate ion influx (2). Although glycine was originally suggested as the NMDA receptor coagonist, recent data indicate that endogenous D-serine is a physiologically relevant NMDA receptor ligand at the coagonist site. D-Serine is present at high levels in the brain, with little levels in peripheral tissues (3-5). Destruction of endogenous D-serine by D-amino-acid oxidase in hippocampal cultures promotes a decrease in NMDA receptor responses (6). Likewise, NMDA receptor-mediated responses in the retina and induction of long-term hippocampal potentiation are also diminished by removing D-serine (7,8). Very recently, D-serine was shown to be required for granule cell migration in the developing cerebellum (9). It has been proposed that Bergman glial cells release D-serine and enhance cell migration through activation of NMDA receptors in migrating granule cells (9). In hippocampal organotypic slice cultures, endogenous D-serine was shown to be the dominant coagonist for NMDA receptor-elicited neurotoxicity, mediating virtually all cell death elicited by NMDA (10).D-Serine is synthesized from L-serine by serine racemase, a brain enriched enzyme (11-13). Serine racemase activity is stimulated by ATP, and the enzyme also catalyzes deamination of serine into pyruvate and ammonia (14, 15). Both D-serine and serine racemase were shown previously to be enriched in astrocytes (13, 16). Purified astrocytic cultures release D-serine following (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor activation (16 -18) and through an amino acid exchange mechanism by the neutral amino acid transporter ASCT (17). It has been proposed that D-serine released from astrocytes that ensheath the synapse will stimulate nearby neuronal NMDA receptors (16).The evidence that D-serine possesses a target receptor as well as a biosynthetic and degradative apparatus implies that D-serine is an important transmitter/neuromodulator in the brain (5, 19). On the other hand, the glial localization of D-serine is not compatible with the classical definition of neurotransmitter, which should be present in neurons. We have explored a possible neuronal localization of D-serine and serine racemase utilizing biochemical methods in cell cultures and new antibodies against D-serine and serine racemase. We demonstrate the unambiguous presence of serine racemase and D-serine in neurons. Neuronal release of D-serine mediates a significant fraction of NMDAelicited excitotoxicity in cortical cultures. Our data indicate that neuronal D-serine may play an important role in NMDA receptor activation, such as occurs in neurotoxicity. EXPERIMENTAL PROCEDURESMaterials-L-Serine and D-serine were purchased from Bachem. Acetonitrile, AMPA, trans-(Ϯ)-1-amino-1,3-cyclopentanedicarboxylic acid, bafilomycin A 1 , DNase I...

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Section: D-serine Synthesis and Serine Racemase In Neurons-mentioning

confidence: 99%

Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors

Kartvelishvily

Shleper

Balan

et al. 2006

Journal of Biological Chemistry

257

269

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“…Later studies on the ability of chromaffin granule ghosts to transport catecholamines by using only electrical potential AP in the absence of ApH argued against the ion trapping model (9). Indeed, Johnson and Scarpa concluded recently that the charge of the transported catecholamine could not be determined from the information available (8).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, this particular aspect of chromaffin granule catecholamine transport, the nature of the transported species, has occupied many investigators (4,(6)(7)(8)(9)(10). Johnson and Scarpa (6,7) proposed that dopamine might be transported into granules as the neutral species, analogous to ammonia equilibration across biological membranes with subsequent -trapping by protonation.…”

Section: Discussionmentioning

confidence: 99%

“…They observed that the Km for norepinephrine declined between pH 6.5 and 8.5, and they interpreted this as due to an increase in the concentration of the uncharged species, the proper substrate. Yet, on the basis of entirely different considerations, Johnson and Scarpa (7) initially claimed that the species transported was most likely neutral, and more recently summarized by saying that a conclusion was not yet possible (8).…”

mentioning

confidence: 99%

“…Many models have been proposed to explain the process, but distinguishing among them has been made difficult by lack of knowledge of whether the neutral, cationic, or anionic catecholamine species is the true substrate (4,(6)(7)(8)(9). Recently, on the basis of observations that both the binding constants for dopamine and serotonin and the calculated cationic fractions were constant between pH 6.8 and 7.6, Knoth et al (10) concluded that the cationic species was translocated.…”

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confidence: 99%

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Chemical evidence that catecholamines are transported across the chromaffin granule membrane as noncationic species.

Ramu¹,

Levine²,

Pollard³

1983

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

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Catecholamines are transported into chromaffin granules by a Mg2+/ATP-driven process under conditions in which the substrate exists primarily as a positively charged or neutral species. In order to distinguish between these two states, we studied the transport properties of a permanently charged quaternary analogue of epinephrine, (R,S)-dimethylepinephrine. We found that this compound was a classical competitive inhibitor of (R)-[3H]norepinephrine uptake, with a K; of 3.8 mM for the racemic form, or 1.9 mM for the R form. However, the [3H]dimethylepinephrine was not transported at all into granules. Our control for steric hindrance as an explanation for deficient translocation was analysis of the transport properties of isoproterenol, a secondary catecholamine with an isopropyl group around the amine residue. (R)-Isoproterenol was an effective competitive inhibitor of (R)-[3H]norepinephrine transport, with a K; of 91 ,uM. In contrast to dimethylepinephrine, (RS)-[3H]isoproterenol was clearly translocated across the granule membrane, with a Km of 123 aiM, or 61.5 IAM for the R isomer. Thus, the positive charge on dimethylepinephrine and not the size of the amine moiety appeared to be responsible for the lack of translocation. We interpret these data to indicate that, although the positively charged species can interact with the transport site, an uncharged species is the one actually transported.Catecholamines are transported into chromaffin granules by a Mg2+/ATP-driven process, which has become increasingly attractive as a general and simple system to analyze chemiosmotic energy coupling to transport (1-5). Many models have been proposed to explain the process, but distinguishing among them has been made difficult by lack of knowledge of whether the neutral, cationic, or anionic catecholamine species is the true substrate (4,(6)(7)(8)(9). Recently, on the basis of observations that both the binding constants for dopamine and serotonin and the calculated cationic fractions were constant between pH 6.8 and 7.6, Knoth et al. (10) concluded that the cationic species was translocated. However, using a similar experimental approach, Scherman and Henry (11) came to the opposite conclusion. They observed that the Km for norepinephrine declined between pH 6.5 and 8.5, and they interpreted this as due to an increase in the concentration of the uncharged species, the proper substrate. Yet, on the basis of entirely different considerations, Johnson and Scarpa (7) initially claimed that the species transported was most likely neutral, and more recently summarized by saying that a conclusion was not yet possible (8).We therefore decided to reinvestigate this question directly by examining the transport properties of a quaternary analogue of epinephrine. The compound we used was (R,S)-dimethylepinephrine (Me2E). * Me2E and its tritium-labeled derivative have the structure shown in Fig. 1 FIG. 1. Structures of Me2E (A) and isoproterenol (B). [3H]Me2E waslabeled at the p carbon (*). The wavy line on isoproterenol in ...

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Evidence for presynaptic antagonism by amantadine of indirectly acting central stimulants

1983

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In mice, amantadine pretreatment (150 mg/kg, but not 10 mg/kg, 2 h prior to testing) markedly inhibited the locomotor stimulation produced by submaximal doses of d-amphetamine, amfonelic acid, methylphenidate, caffeine, memantin, phencyclidine, and cocaine. A 50-mg/kg dose was ineffective in blocking the effects of caffeine and memantin, but blocked the responses to the other five stimulants. Amantadine did not modify the locomotor stimulant effect of apomorphine in reserpinized mice. These results indicate that amantadine acts as a presynaptic antagonist to the above seven stimulants. Even the highest dose of amantadine did not modify the hyperactivity induced in mice by morphine and levorphanol. This result is consistent with evidence showing opiate actions at postsynaptic striatal neurons, sites where presumably amantadine is unable to exert an antagonist effect. Amantadine did not modify the central depressant effects of ethyl alcohol and pentobarbital. Amantadine could be of value as a pharmacological tool in understanding the mode of action of central stimulants, and in the management of stimulant abuse. The present data do not support the currently held view that the antiparkinsonism effect of amantadine results from its ability to potentiate the central effects of dopamine.

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Accumulation of amantadine by isolated chromaffin granules

Cited by 15 publications

References 22 publications

Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors

Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors

Chemical evidence that catecholamines are transported across the chromaffin granule membrane as noncationic species.

Evidence for presynaptic antagonism by amantadine of indirectly acting central stimulants

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