Carrier-mediated release of neurotransmitters

Levi, Giulio; Raiteri, Maurizio

doi:10.1016/0166-2236(93)90010-j

Cited by 345 publications

(239 citation statements)

References 39 publications

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“…The carrier-mediated release does not require energy and is not associated with neuronal conduction (Levi & Raiteri 1993;Vizi 2000). Moreover, protein kinase C-dependent phosphorylation of dopamine transporter can shift the activity of dopamine transporters from supporting inward transport exclusively to an enhanced tendency for amphetamine-evoked efflux (Blakely & Bauman 2000).…”

Section: The Da Transporter In the Brainmentioning

confidence: 99%

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Bergström¹,

Tupala²,

Tiihonen³

2001

Pharmacology & Toxicology

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Much research interest has lately been focused on the dopamine transporter function in brain. Recent findings indicate that dopamine reuptake is more like a highly regulated than a constitutive determinant of dopamine clearance. Positron emission tomography (PET) and single-photon emission tomography (SPET) offer unique methods to study dopamine transporter function. Results from in vivo PET and SPET studies correspond well with in vitro studies performed on post mortem human brain tissue. Considering some of the variances between in vitro and in vivo receptor binding phenomena it may be that the role of a compound to alter binding to monoamine uptake sites in vitro does not indicate its potential to affect monoamine transporters after administration in vivo. This discrepancy may be better understood taking into account recent studies indicating the possibility of a rapid regulation of transporter function and surface expression. Furthermore, the dopamine transporter is a fruitful target for CNS drug discovery. Fundamental nature of drug actions in vivo may be studied using demonstrated in vitro and in vivo imaging methods.

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Section: The Da Transporter In the Brainmentioning

confidence: 99%

Dopamine Transporter in vitro Binding and in vivo Imaging in the Brain

Bergström¹,

Tupala²,

Tiihonen³

2001

Pharmacology & Toxicology

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“…Reversal is not unique to the GABA transporter (Nicholls and Attwell, 1990;Levi and Raiteri, 1993), but it is possible that the threshold for reversal of the GABA transporter is lower than for other transporters (Attwell et al, 1993). A low threshold for reversal may be related to the inhibitory role of the GABAergic system.…”

Section: Functional Role Of the Gaba Transportermentioning

confidence: 99%

“…However, many transporters can also reverse, causing the release of neurotransmitter in a calcium-independent manner (Nicholls and Attwell, 1990;Attwell et al, 1993;Levi and Raiteri, 1993). For example, the GABA transporter reverses in response to depolarization or an increase in [Na ϩ ] i (Moscowitz and Cutler, 1980;Bernath and Zigmond, 1988;Pin and Bockaert, 1989;Saransaari and Oja, 1992;Belhage et al, 1993;Cammack and Schwartz, 1993;Cammack et al, 1994).…”

Section: Abstract: Seizure; Epilepsy; Vigabatrin; Synapse; Nonvesicumentioning

confidence: 99%

“…For example, calcium-independent GABA release has been induced by an increase in [K ϩ ] o to Ͼ50 mM, by 100 M glutamate, and by nipecotate (NPA) (Moscowitz and Cutler, 1980;Pin and Bockaert, 1989;Turner and Goldin, 1989;Solis and Nicoll, 1992;Belhage et al, 1993;Honmou et al, 1995). Probably for this reason, reversal of the GABA transporter has been considered to be important only during pathological conditions such as ischemia (Nicholls and Attwell, 1990;Levi and Raiteri, 1993). However, carrier-mediated GABA release can occur in response to presynaptic stimulation (Schwartz, 1987;Bernath and Zigmond, 1988) and also can occur in response to an elevation in [K ϩ ] o from 3 to 12 mM (Gaspary et al, 1998), a level of [K ϩ ] o that is reached in vivo during neuronal firing (Krnjevic et al, 1980;Somjen and Giacchino, 1985) and during seizures (Fisher et al, 1976).…”

Section: Abstract: Seizure; Epilepsy; Vigabatrin; Synapse; Nonvesicumentioning

confidence: 99%

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GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

2001

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The GABA transporter can reverse with depolarization, causing nonvesicular GABA release. However, this is thought to occur only under pathological conditions. Patch-clamp recordings were made from rat hippocampal neurons in primary cell cultures. Inhibition of GABA transaminase with the anticonvulsant ␥-vinyl GABA (vigabatrin; 0.05-100 M) resulted in a large leak current that was blocked by bicuculline (50 M). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transporter antagonist SKF-89976a (5 M). These results indicate that vigabatrin induces spontaneous GABA efflux from neighboring cells via reversal of GABA transporters, subsequently leading to the stimulation of GABA A receptors on the recorded neuron. The leak current increased slowly over 4 d of treatment with 100 M vigabatrin, at which time it reached an equivalent conductance of 9.0 Ϯ 4.9 nS. Blockade of glutamic acid decarboxylase with semicarbazide (2 mM) decreased the leak current that was induced by vigabatrin by 47%. In untreated cells, carrier-mediated GABA efflux did not occur spontaneously but was induced by an increase in [K ϩ ] o from 3 to as little as 6 mM. Vigabatrin enhanced this depolarization-evoked nonvesicular GABA release and also enhanced the heteroexchange release of GABA induced by nipecotate. Thus, the GABA transporter normally operates near its equilibrium and can be easily induced to reverse by an increase in cytosolic [GABA] or mild depolarization. We propose that this transporter-mediated nonvesicular GABA release plays an important role in neuronal inhibition under both physiological and pathophysiological conditions and is the target of some anticonvulsants.

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“…Like other amphetamines, FEN and dFEN release endogenous 5-HT by a carrier-mediated mechanism involving SERT proteins in cell membranes (Berger et al 1992;Schuldiner et al 1993). SERTs play a pivotal role in the release process because they serve as 'gateways' for the flow of drug molecules into the cell in exchange for 5-HT molecules that flow out (Levi and Raiteri 1993;Rudnick 1997). Interestingly, 5-HT-selective reuptake inhibitors (SSRIs) such as fluoxetine are known to prevent acute 5-HT release and long-term 5-HT depletion produced by FEN administration (Clineschmidt et al 1978;Steranka and Sanders-Bush 1979;Sabol et al 1992).…”

mentioning

confidence: 99%