Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas <i>nucleus accumbens</i> and <i>globus pallidus</i>

Molnár, Tünde; Fekete, Erzsébet Kútiné; Kardos, Julianna; Simon‐Trompler, Edit; Palkovits, Miklós; Emri, Zsuzsa

doi:10.1002/jnr.20867

Cited by 14 publications

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“…Identity of SUC-sensitive GHB [5] and GHB-sensitive SUC [4] binding sites raised the possibility to relate SUC and different GHB actions [47-50]. Importantly, the binding site of GHB/SUC interacts with CBX [4-6], a blocker of gap-junctions that are major players of astroglial Ca 2+ signalling [51].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…His103 was protonated at both N atoms, corresponding to an acidic environment. SUC and GHB ligands were prepared from the PDB database (SUC ligand of 2WBP; Helmetag et al, 2009) in their protonated form according to the acidic pH of the receptor binding (Molnár et al, 2006, 2008a,b). Ligands were minimized in SYBYL until the RMS gradient reached 0.01 kcal/mol/Å.…”

Section: Methodsmentioning

confidence: 99%

“…A common binding site for SUC and gamma-hydroxybutyrate (GHB), that enters the citric acid cycle via SUC (Rumigny et al, 1981) has been disclosed previously (Molnár et al, 2006, 2008a,b). Additionally, intracellular Ca 2+ store-reliant astroglial Ca 2+ transients evoked by GHB have been described in the NAc (Molnár et al, 2009).…”

Section: Introductionmentioning

confidence: 94%

“…We have shown that this action of GHB is GABA B receptor independent, since it remains in mice lacking functional GABA B receptors unlike the majority of GHB-mediated physiological and pharmacological actions including “rape drug effects” that were demonstrated to be dependent on GABA B receptors (Kaupmann et al, 2003; Wong et al, 2004). Only a few study addressed GHB receptor dependent GHB actions (Molnár et al, 2006, 2009), although high-affinity GHB binding sites were demonstrated in mice lacking GABA B receptors (Kaupmann et al, 2003) and the function of endogenous GHB has never been clearly defined. A number of studies indicate that in addition to its neurotransmitter/neuromodulatory role, GHB may function in the control of physiological states, like sleep and hibernation.…”

Section: Introductionmentioning

confidence: 99%

“…The molecular identity of the GHB receptor has not been identified yet satisfactorily, the putative GHB receptor mRNA showed different brain distribution than the native GHB receptors (Andriamampandry et al, 2003, 2007). A binding site recognizing GHB and SUC has been disclosed in the NAc (Molnár et al, 2006, 2008a,b), its relationship with the G protein-coupled heptahelical kidney SUC receptor (SUCNR1:GPCR91, He et al, 2004) has not previously been conjectured.…”

Section: Introductionmentioning

confidence: 99%

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Activation of astroglial calcium signaling by endogenous metabolites succinate and gamma-hydroxybutyrate in the nucleus accumbens

et al. 2011

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Accumulating evidence suggests that different energy metabolites play a role not only in neuronal but also in glial signaling. Recently, astroglial Ca2+ transients evoked by the major citric acid cycle metabolite succinate (SUC) and gamma-hydroxybutyrate (GHB) that enters the citric acid cycle via SUC have been described in the brain reward area, the nucleus accumbens (NAc). Cells responding to SUC by Ca2+ transient constitute a subset of ATP-responsive astrocytes that are activated in a neuron-independent way. In this study we show that GHB-evoked Ca2+ transients were also found to constitute a subset of ATP-responsive astrocytes in the NAc. Repetitive Ca2+ dynamics evoked by GHB suggested that Ca2+ was released from internal stores. Similarly to SUC, the GHB response was also characterized by an effective concentration of 50 μM. We observed that the number of ATP-responsive cells decreased with increasing concentration of either SUC or GHB. Moreover, the concentration dependence of the number of ATP-responsive cells were highly identical as a function of both [SUC] and [GHB], suggesting a mutual receptor for SUC and GHB, therefore implying the existence of a distinct GHB-recognizing astroglial SUC receptor in the brain. The SUC-evoked Ca2+ signal remained in mice lacking GABAB receptor type 1 subunit in the presence and absence of the N-Methyl-d-Aspartate (NMDA) receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV), indicating action mechanisms independent of the GABAB or NMDA receptor subtypes. By molecular docking calculations we found that residues R99, H103, R252, and R281 of the binding crevice of the kidney SUC-responsive membrane receptor SUCNR1 (GPCR91) also predict interaction with GHB, further implying similar GHB and SUC action mechanisms. We conclude that the astroglial action of SUC and GHB may represent a link between brain energy states and Ca2+ signaling in astrocytic networks.

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γ‐Hydroxybutyrate binds to the synaptic site recognizing succinate monocarboxylate: A new hypothesis on astrocyte–neuron interaction via the protonation of succinate

Molnár

Barabás

Héja

et al. 2008

J of Neuroscience Research

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Succinate (SUC), a citrate (CIT) cycle intermediate, and carbenoxolone (CBX), a gap junction inhibitor, were shown to displace [3H]gamma-hydroxybutyrate ([3H]GHB), which is specifically bound to sites present in synaptic membrane subcellular fractions of the rat forebrain and the human nucleus accumbens. Elaboration on previous work revealed that acidic pH-induced specific binding of [3H]SUC occurs, and it has been shown to have a biphasic displacement profile distinguishing high-affinity (K(i,SUC) = 9.1 +/- 1.7 microM) and low-affinity (K(i,SUC) = 15 +/- 7 mM) binding. Both high- and low- affinity sites were characterized by the binding of GHB (K(i,GHB) = 3.9 +/- 0.5 microM and K(i,GHB) = 5.0 +/- 2.0 mM) and lactate (LAC; K(i,LAC) = 3.9 +/- 0.5 microM and K(i,LAC) = 7.7 +/- 0.9 mM). Ligands, including the hemiester ethyl-hemi-SUC, and the gap junction inhibitors flufenamate, CBX, and the GHB binding site-selective NCS-382 interacted with the high-affinity site (in microM: K(i,EHS) = 17 +/- 5, K(i,FFA) = 24 +/- 13, K(i,CBX) = 28 +/- 9, K(i,NCS-382) = 0.8 +/- 0.1 microM). Binding of the Na+,K+-ATPase inhibitor ouabain, the proton-coupled monocarboxylate transporter (MCT)-specific alpha-cyano-hydroxycinnamic acid (CHC), and CIT characterized the low-affinity SUC binding site (in mM: K(i,ouabain) = 0.13 +/- 0.05, K(i,CHC) = 0.32 +/- 0.07, K(i,CIT) = 0.79 +/- 0.20). All tested compounds inhibited [3H]SUC binding in the human nucleus accumbens and had K(i) values similar to those observed in the rat forebrain. The binding process can clearly be recognized as different from synaptic and mitochondrial uptake or astrocytic release of SUC, GHB, and/or CIT by its unique GHB selectivity. The transient decrease of extracellular SUC observed during epileptiform activity suggested that the function of the synaptic target recognizing protonated succinate monocarboxylate may vary under different (patho)physiological conditions. Furthermore, we put forward a hypothesis on the synaptic activity-regulated signaling between astrocytes and neurons via SUC protonation.

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Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

Cited by 14 publications

References 47 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

Activation of astroglial calcium signaling by endogenous metabolites succinate and gamma-hydroxybutyrate in the nucleus accumbens

γ‐Hydroxybutyrate binds to the synaptic site recognizing succinate monocarboxylate: A new hypothesis on astrocyte–neuron interaction via the protonation of succinate

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