The Triakontatetraneuropeptide (TTN) Stimulates Thymidine Incorporation in Rat Astrocytes Through Peripheral‐Type Benzodiazepine Receptors

Gandolfo, Pierrick; Patte, Christine; Leprince, Jérôme; Rego, Jean-Luc do; Mensah‐Nyagan, Ayikoe Guy; Vaudry, Hubert; Tonon, Marie‐Christine

doi:10.1046/j.1471-4159.2000.0750701.x

Cited by 21 publications

(21 citation statements)

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“…It has previously been shown that TTN is one of the major forms of endozepines released by cultured astroglial cells (Patte et al, 1999;Gandolfo et al, 2000). We now demonstrate that TTN, acting through PBR, causes calcium influx through L-type calcium channels in cultured rat astrocytes.…”

Section: Discussionsupporting

confidence: 54%

“…In the brain, the DBI gene is predominantly expressed in glial cells (Tong et al, 1991;Lihrmann et al, 1994;Alho et al, 1995) and the occurrence of DBI-derived peptides has been visualized in astrocytes by immunohistochemistry (Tonon et al, 1990;Malagon et al, 1993;Vidnyanszky et al, 1994;Do-Ré go et al, 2001). It has also been shown that cultured rat glial cells contain and secrete DBI-related peptides (Lamacz et al, 1996;Patte et al, 1999), and that TTN is the major form of endozepines released by astroglial cells (Gandolfo et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Despite their name, PBR are also present in the CNS (Moynagh et al, 1991); in particular, high density of receptors are found in glial cells (Benavides et al, 1990;Itzhak et al, 1993). In addition, it has been shown that TTN, acting on PBR, increases neurosteroid synthesis in C6 glioma cells and thymidine incorporation in cultured rat astrocytes (Gandolfo et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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The triakontatetraneuropeptide TTN increases [Ca²⁺]_i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

Gandolfo

Louiset

Patte

et al. 2001

Glia

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Astrocytes synthesize a series of regulatory peptides called endozepines, which act as endogenous ligands of benzodiazepine receptors. We have recently shown that one of these endozepines, the triakontatetraneuropeptide TTN, stimulates DNA synthesis in astroglial cells. The purpose of the present study was to determine the mechanism of action of TTN on cultured rat astrocytes. Binding of the peripheral-type benzodiazepine receptor ligand [3H]Ro5-4864 to intact astrocytes was displaced by TTN, whereas its C-terminal fragment (TTN[17-34], the octadecaneuropeptide ODN) did not compete for [3H]Ro5-4864 binding. Microfluorimetric measurement of cytosolic calcium concentrations ([Ca2+]i) with the fluorescent probe indo-1 showed that TTN (10(-10) to 10(-6) M) provokes a concentration-dependent increase in [Ca2+]i in cultured astrocytes. Simultaneous administration of TTN (10(-8) M) and Ro5-4864 (10(-5) M) induced an increase in [Ca2+]i similar to that obtained with Ro5-4864 alone. In contrast, the effects of TTN (10(-8) M) and ODN (10(-8) M) on [Ca2+]i were strictly additive. Chelation of extracellular Ca2+ by EGTA (6 mM) or blockage of Ca2+ channels with Ni2+ (2 mM) abrogated the stimulatory effect of TTN. The calcium influx evoked by TTN (10(-7) M) or by Ro5-4864 (10(-5) M) was not affected by the N- and T-type calcium channel blockers omega-conotoxin (10(-6) M) and mibefradil (10(-6) M), but was significantly reduced by the L-type calcium channel blocker nifedipine (10(-7) M). Patch-clamp studies showed that, at negative potentials, TTN (10(-7) M) induced a sustained depolarization. Reduction of the chloride concentration in the extracellular solution shifted the reversal potential from 0 mV to a positive potential. These data show that TTN, acting through peripheral-type benzodiazepine receptors, provokes chloride efflux, which in turn induces calcium influx via L-type calcium channels in rat astrocytes.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The triakontatetraneuropeptide TTN increases [Ca²⁺]_i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

Gandolfo

Louiset

Patte

et al. 2001

Glia

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“…The release of endozepines by cultured glial cells can be inhibited by GABA or somatostatin (14,15) and stimulated by beta-amyloid peptide or pituitary adenylate cyclase-activating polypeptide (16)(17)(18). DBI peptides also have been demonstrated to affect astrocytic function via actions on the mitochondrial benzodiazepine receptor, also known as 18-kDa translocator protein, which influences GABA receptor activation through modulation of neurosteroid production (19,20). Endogenous regulation of endozepine actions by native glial cells and subsequent effects on synaptic inhibition remain to be demonstrated.…”

mentioning

confidence: 99%

Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling

Christian

Huguenard

2013

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

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Emerging evidence indicates that diazepam-binding inhibitor (DBI) mediates an endogenous benzodiazepine-mimicking (endozepine) effect on synaptic inhibition in the thalamic reticular nucleus (nRT). Here we demonstrate that DBI peptide colocalizes with both astrocytic and neuronal markers in mouse nRT, and investigate the role of astrocytic function in endozepine modulation in this nucleus by testing the effects of the gliotoxin fluorocitrate (FC) on synaptic inhibition and endozepine signaling in the nRT using patch-clamp recordings. FC treatment reduced the effective inhibitory charge of GABA A receptor (GABA A R)-mediated spontaneous inhibitory postsynaptic currents in WT mice, indicating that astrocytes enhance GABA A R responses in the nRT. This effect was abolished by both a point mutation that inhibits classical benzodiazepine binding to GABA A Rs containing the α3 subunit (predominant in the nRT) and a chromosomal deletion that removes the Dbi gene. Thus, astrocytes are required for positive allosteric modulation via the α3 subunit benzodiazepine-binding site by DBI peptide family endozepines. Outside-out sniffer patches pulled from neurons in the adjacent ventrobasal nucleus, which does not contain endozepines, show a potentiated response to laser photostimulation of caged GABA when placed in the nRT. FC treatment blocked the nRT-dependent potentiation of this response, as did the benzodiazepine site antagonist flumazenil. When sniffer patches were placed in the ventrobasal nucleus, however, subsequent treatment with FC led to potentiation of the uncaged GABA response, suggesting nucleus-specific roles for thalamic astrocytes in regulating inhibition. Taken together, these results suggest that astrocytes are required for endozepine actions in the nRT, and as such can be positive modulators of synaptic inhibition.thalamus | glia | uncaging | electrophysiology | epilepsy

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“…Fourth, the selective PBR antagonist PK11195 markedly reduced [ 3 H]thymidine incorporation in rat astrocytes induced by low-dose triakontatetraneuropeptide (TTN), a DBI-derived peptide. In contrast, the selective CBR antagonist flumazenil did not significantly modify the effect of TTN (32). Further research is, however, needed to elucidate whether the inhibition of salivary secretion by repetitive administration of DZP is attenuated by simultaneous treatment with a peripheral-type benzodiazepine antagonist.…”

Section: +mentioning

confidence: 88%

Diazepam Enhances Production of Diazepam-Binding Inhibitor (DBI), a Negative Saliva Secretion Regulator, Localized in Rat Salivary Gland

et al. 2011

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Abstract. Peripheral-type benzodiazepine receptor (PBR) and central-type benzodiazepine receptor (CBR) in salivary gland play a role in the inhibitory regulation of salivary secretion in rodents. Diazepam-binding inhibitor (DBI), an endogenous ligand for PBR, produces neurosteroids, which modulate CBR activity. In this study, we investigated the effect of repetitive administration of diazepam (DZP) on salivary secretion and expression of DBI mRNA and peptide. Moreover, mRNA expression of PBR and pituitary adenylate cyclase-activating polypeptide (PACAP), a transcriptional regulator for DBI promoter, was evaluated after repetitive administration of DZP. Repetitive administration, but not single administration, of 0.4 mg/kg DZP caused inhibition of salivary secretion and enhanced expression of DBI, PACAP, and PBR mRNA in rat salivary gland, with an increase in production of DBI peptide. These results suggest that repetitive administration of DZP stimulates DBI production, which may result in an increase in the suppressive effect of DZP on salivary secretion.

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The Triakontatetraneuropeptide (TTN) Stimulates Thymidine Incorporation in Rat Astrocytes Through Peripheral‐Type Benzodiazepine Receptors

Cited by 21 publications

References 51 publications

The triakontatetraneuropeptide TTN increases [Ca²⁺]_i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

The triakontatetraneuropeptide TTN increases [Ca²⁺]_i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling

Diazepam Enhances Production of Diazepam-Binding Inhibitor (DBI), a Negative Saliva Secretion Regulator, Localized in Rat Salivary Gland

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The Triakontatetraneuropeptide (TTN) Stimulates Thymidine Incorporation in Rat Astrocytes Through Peripheral‐Type Benzodiazepine Receptors

Cited by 21 publications

References 51 publications

The triakontatetraneuropeptide TTN increases [Ca2+]i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

The triakontatetraneuropeptide TTN increases [Ca2+]i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

Astrocytes potentiate GABAergic transmission in the thalamic reticular nucleus via endozepine signaling

Diazepam Enhances Production of Diazepam-Binding Inhibitor (DBI), a Negative Saliva Secretion Regulator, Localized in Rat Salivary Gland

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The triakontatetraneuropeptide TTN increases [Ca²⁺]_i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors

The triakontatetraneuropeptide TTN increases [Ca²⁺]_i in rat astrocytes through activation of peripheral‐type benzodiazepine receptors