Validation of high-affinity binding sites for succinic acid through distinguishable binding of gamma-hydroxybutyric acid receptor-specific NCS 382 antipodes

Molnár, Tünde; Visy, Júlia; Simon, Ágnes; Moldvai, István; Temesvári-Major, Eszter; Dörnyei, Gábor; Fekete, Erzsébet Kútiné; Kardos, Julianna

doi:10.1016/j.bmcl.2008.08.083

Cited by 10 publications

(15 citation statements)

References 11 publications

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“…Binding of CBX to SUC receptor [4-6], however, could be accounted for some blockade of ATP-driven Ca 2+ signal propagation as detailed below.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we also showed that binding sites for GHB are shared with citric acid cycle intermediate succinic acid (SUC) and the gap-junction blocker carbenoxolone hemisuccinate (CBX), as disclosed in NAc membrane homogenates isolated from rat and human brain tissues [4-6]. These findings raised the possibility that SUC, similarly to GHB may also evoke Ca 2+ transients in NAc astrocytes.…”

Section: Introductionmentioning

confidence: 94%

“…In astrocytes of the brain reward area, the nucleus accumbens (NAc; [ 1 ]), γ-hydroxybutyric acid (GHB; [ 2 ]) evoked intracellular store-reliant Ca 2+ transients, independently of neuronal activity [ 3 ]. Previously, we also showed that binding sites for GHB are shared with citric acid cycle intermediate succinic acid (SUC) and the gap-junction blocker carbenoxolone hemisuccinate (CBX), as disclosed in NAc membrane homogenates isolated from rat and human brain tissues [ 4 - 6 ]. These findings raised the possibility that SUC, similarly to GHB may also evoke Ca 2+ transients in NAc astrocytes.…”

Section: Introductionmentioning

confidence: 99%

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Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

et al. 2011

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BackgroundAccumulating evidence suggests that glial signalling is activated by different brain functions. However, knowledge regarding molecular mechanisms of activation or their relation to neuronal activity is limited. The purpose of the present study is to identify the characteristics of ATP-evoked glial signalling in the brain reward area, the nucleus accumbens (NAc), and thereby to explore the action of citric acid cycle intermediate succinate (SUC).ResultsWe described the burst-like propagation of Ca2+ transients evoked by ATP in acute NAc slices from rat brain. Co-localization of the ATP-evoked Ca2+ signalling with immunoreactivities of the astroglia-specific gap junction forming channel protein connexin43 (Cx43) and the glial fibrillary acidic protein (GFAP) indicated that the responsive cells were a subpopulation of Cx43 and GFAP immunoreactive astrocytes. The ATP-evoked Ca2+ transients were present under the blockade of neuronal activity, but were inhibited by Ca2+ store depletion and antagonism of the G protein coupled purinergic P2Y1 receptor subtype-specific antagonist MRS2179. Similarly, Ca2+ transients evoked by the P2Y1 receptor subtype-specific agonist 2-(Methylthio)adenosine 5'-diphosphate were also blocked by MRS2179. These characteristics implied that intercellular Ca2+ signalling originated from the release of Ca2+ from internal stores, triggered by the activation of P2Y1 receptors. Inhibition by the gap junction blockers carbenoxolone and flufenamic acid and by an antibody raised against the gating-associated segment of Cx43 suggested that intercellular Ca2+ signalling proceeded through gap junctions. We demonstrated for the first time that extracellular SUC also evoked Ca2+ transients (EC50 = 50-60 μM) in about 15% of the ATP-responsive NAc astrocytes. By contrast to glial cells, electrophysiologically identified NAc neurons surrounded by ATP-responsive astrocytes were not activated simultaneously.ConclusionsWe concluded, therefore, that ATP- and SUC-sensitive Ca2+ transients appear to represent a signalling layer independent of NAc neurons. This previously unrecognised glial action of SUC, a major cellular energy metabolite, may play a role in linking metabolism to Ca2+ signalling in astrocytic networks under physiological and pathological conditions such as exercise and metabolic diseases.

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“…Binding of CBX to SUC receptor [4-6], however, could be accounted for some blockade of ATP-driven Ca 2+ signal propagation as detailed below.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

et al. 2011

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“…Yet, these considerations and findings may allow speculations on a possible functional link between the danger signal Sucn [202] and reward/addiction processes. Both the coincidence and synergy of ATP- and Sucn/GHB-responsive astrocytic calcium transients together with the presence of high-affinity Sucn/GHB recognizing sites in the NAc [128–133] strongly imply the involvement of a Sucn-responsive astrocytic target. This positive feedback mechanism supports the nucleation-type model [118] of the astrocyte network activation dynamics in the NAc.…”

Section: Modulation Of Inhibitory Signaling By Converging Metabolic Amentioning

confidence: 99%

Molecular Plasticity of the Nucleus Accumbens Revisited—Astrocytic Waves Shall Rise

et al. 2019

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Part of the ventral striatal division, the nucleus accumbens (NAc) drives the circuit activity of an entire macrosystem about reward like a “flagship,” signaling and leading diverse conducts. Accordingly, NAc neurons feature complex inhibitory phenotypes that assemble to process circuit inputs and generate outputs by exploiting specific arrays of opposite and/or parallel neurotransmitters, neuromodulatory peptides. The resulting complex combinations enable versatile yet specific forms of accumbal circuit plasticity, including maladaptive behaviors. Although reward signaling and behavior are elaborately linked to neuronal circuit activities, it is plausible to propose whether these neuronal ensembles and synaptic islands can be directly controlled by astrocytes, a powerful modulator of neuronal activity. Pioneering studies showed that astrocytes in the NAc sense citrate cycle metabolites and/or ATP and may induce recurrent activation. We argue that the astrocytic calcium, GABA, and Glu signaling and altered sodium and chloride dynamics fundamentally shape metaplasticity by providing active regulatory roles in the synapse- and network-level flexibility of the NAc.

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“…Because of continued interest in this important area, we decided to radiolabel GHB at high specific activity and accomplished this quite easily by the catalytic tritiation of 2(5H) furanone ( 37 ), obtaining 38 (Scheme ) and characterizing the product by tritium NMR as well 151. Radioligand 38 continues to be useful for elucidating details of the purported GHB receptor 152, 153…”

Section: Other Gaba Agentsmentioning

confidence: 99%

GABAergic radioligands labelled with tritium

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2010

Labelled Comp Radiopharmac

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Validation of high-affinity binding sites for succinic acid through distinguishable binding of gamma-hydroxybutyric acid receptor-specific NCS 382 antipodes

Cited by 10 publications

References 11 publications

Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

Molecular Plasticity of the Nucleus Accumbens Revisited—Astrocytic Waves Shall Rise

GABAergic radioligands labelled with tritium

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