Intrasynaptosomal free calcium levels in rat forebrain synaptosomes: modulation by sigma (σ) receptor ligands

Brent, Paul J.; Saunders, Heather; Dunkley, Peter R.

doi:10.1016/0304-3940(96)12711-7

Cited by 15 publications

(17 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding demonstrates that the mechanism of action of this neurosteroid involves an elevation in [Ca 2ϩ ] i . This finding is consistent with several reports demonstrating that receptors regulate [Ca 2ϩ ] i (35,45,(47)(48)(49). It is also in agreement with recent reports that a significant percentage of miniature synaptic currents in hippocampal neurons are regulated by changes in [Ca 2ϩ ] i in axonal terminals (50,51).…”

Section: Role Of 1 -Like Receptors In the Mechanism Of Action Of Pregsupporting

confidence: 83%

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

Meyer¹,

Carta²,

Partridge³

et al. 2002

Journal of Biological Chemistry

126

View full text Add to dashboard Cite

Pregnenolone sulfate (PREGS), one of the most abundantly produced neurosteroids in the mammalian brain, improves cognitive performance in rodents. The mechanism of this effect has been attributed to its allosteric modulatory actions on glutamate-and ␥-aminobutyric acid-gated ion channels. Here we report a novel effect of PREGS that could also mediate some of its actions in the nervous system. We found that PREGS induces a robust potentiation of the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) mediated by ␣-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in cultured hippocampal neurons. PREGS also decreased paired pulse facilitation of autaptic EPSCs evoked by depolarization, indicating that it modulates glutamate release probability presynaptically. PREGS potentiation of mEPSCs was mimicked by dehydroepiandrosterone sulfate and (؉)-pentazocine but not by (؊)-pentazocine, the synthetic (؊)-enantiomer of PREGS or the inactive steroid isopregnanolone. The receptor antagonists, haloperidol and BD-1063, blocked the effect of PREGS on mEPSCs, as did pertussis toxin and the membrane-permeable Ca 2؉ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid (acetoxymethyl) ester. These results suggest that PREGS increases spontaneous glutamate release via activation of a presynaptic G i/o -coupled receptor and an elevation in intracellular Ca 2؉ levels. We postulate that presynaptic actions of neurosteroids have a role in the maturation and/or maintenance of synaptic networks and the processing of information in the central nervous system.

show abstract

Section: Role Of 1 -Like Receptors In the Mechanism Of Action Of Pregsupporting

confidence: 83%

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

Meyer¹,

Carta²,

Partridge³

et al. 2002

Journal of Biological Chemistry

126

View full text Add to dashboard Cite

show abstract

“…Ligand activation of 1 receptors elicited a dose-dependent reduction in intrasynaptosomal free calcium levels (Brent et al, 1996). Presynaptic internal Ca 2ϩ stores are known to modulate mIPSC frequency and GABA release (Bardo et al, 2002); thus, it is possible that the presynaptic effect of PS occurred by mobilizing internal Ca 2ϩ stores.…”

Section: Discussionmentioning

confidence: 99%

A Presynaptic Action of the Neurosteroid Pregnenolone Sulfate on GABAergic Synaptic Transmission

Mtchedlishvili¹

2003

Molecular Pharmacology

View full text Add to dashboard Cite

The endogenous neurosteroid pregnenolone sulfate (PS) is known to enhance memory and cognitive function at nanomolar concentrations. However, the effect of these low concentrations on synaptic transmission has not been previously studied. The effects of PS on GABA A receptor-mediated inhibitory postsynaptic currents were studied in cultured hippocampal pyramidal neurons. Concentrations of PS similar to those endogenous in the hippocampus (10 -30 nM) reduced the frequency of both action potential-dependent (spontaneous inhibitory postsynaptic current) and -independent (miniature inhibitory postsynaptic current; mIPSC) inhibitory postsynaptic currents. This effect of PS was mimicked by the selective 1 receptor agonist [2S-(2␣,6␣,11R]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride [(ϩ)-SKF 10047] and blocked the specific 1 receptor antagonists 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) and haloperidol and by pertussis toxin. The GABA B antagonist baclofen and the metabotropic glutamate receptor antagonist (R,S)-a-cyclopropyl-4-phosphonophenylglycine had no effect on the PS-mediated inhibition of mIPSC frequency. The postsynaptic effects of PS occurred at micromolar concentrations but not at nanomolar concentrations. A comparison of the pre-and postsynaptic effects of PS demonstrated that it was 100-fold more potent in inhibiting presynaptic GABAergic synaptic mechanisms than GABA A receptors. These studies demonstrate that concentrations of PS, similar to those endogenous in the hippocampus, inhibit GABAergic synaptic transmission by a presynaptic effect. PS causes specific activation of G protein-coupled 1 receptors, resulting in modulation of both action potential-dependent and -independent IPSCs. These findings improve our understanding of the physiological function of PS.

show abstract

“…Several of these studies (Brent et al, 1996;Gonzalez and Werling, 1997;Hayashi et al, 2000) proposed that 1 site-preferential (ϩ)-benzomorphans behave as agonists. In contrast, …”

Section: Introductionmentioning

confidence: 99%

“…Previous reports have associated -site ligands with calcium homeostasis (Brent et al, 1996;Hayashi et al, 2000;Hayashi and Su, 2001). -site ligands can influence [ 3 H]dopamine and [ 3 H]norepinephrine (NE) release from rat brain slices, acting, at least partially, presynaptically (Gonzalez-Alvear and Werling, 1995;Gonzalez and Werling, 1997).…”

mentioning

confidence: 97%

“…Several of these studies (Brent et al, 1996;Gonzalez and Werling, 1997;Hayashi et al, 2000) proposed that 1 site-preferential (ϩ)-benzomorphans behave as agonists. In contrast, phenyl]ethylamine HCl] (Tanaka et al, 1995) and DuP 734 (1-(cyclopropylmethyl)-4-(2Ј-(4Љ-fluorophenyl)-2Ј-oxoethyl) piperidine HBr) (Gonzalez-Alvear and Werling, 1995), which have no effects by themselves but reverse the effects of 1 -site agonists, are defined as antagonists.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Ocular Hypotensive Action of Topical Flunarizine in the Rabbit: Role of ς₁Recognition Sites

Campana

Bucolo

Murari

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

In a previous study we ascertained the presence of 1 and 2 recognition sites in the rabbit iris-ciliary body, an ocular structure involved in aqueous humor production and drainage. We characterized the 1 sites using the preferential ligand (ϩ)-pentazocine, which caused a significant reduction of intraocular pressure (IOP). In the present study, flunarizine, a calcium channel blocker with a complex pharmacological profile, bound to 1 sites expressed in the iris-ciliary body with moderate affinity (K i ϭ 68 nM). Unilateral topical flunarizine (0.01-0.1%) caused a dose-related reduction of IOP in ocular normotensive rabbits and in the ␣-chymotrypsin model of ocular hypertension, without altering the IOP of the contralateral eye. This activity was blocked by the 1 site antagonist NE-100 [N,Ndipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine HCl] which, by itself, had no effect on IOP. Detection of flunarizine in rabbit iris-ciliary body homogenates, after topical instillation, showed that it adequately penetrates the rabbit eye. To investigate mechanisms that may contribute to ocular hypotension induced by 1 agonists, we carried out in vitro studies on the isolated rabbit iris-ciliary body. Sigma () recognition sites are a unique class of binding sites, heterogeneously distributed in the nervous system and in peripheral organs, that presumably serve as receptors for some unidentified endogenous ligand (Walker et al., 1990;Quiron et al., 1992). The recognition sites bind an array of structural classes of compounds including haloperidol, 1,3-di-O-tolylguanidine (DTG), and (ϩ)-benzomorphans, such as (ϩ)-pentazocine and (ϩ)-N-allylnormetazocine (Su and Junien, 1994). On the basis of biochemical and radioligand binding data, recognition sites have been classified into at least two types, 1 and 2 (Quiron et al., 1992). The 1 recognition sites display preferential affinity and stereoselectivity for (ϩ)-benzomorphans . A 1 binding protein has been cloned (Hanner et al., 1996), and its sequence shows significant similarities with sterol C 8 -C 7 isomerases from fungi.The functional role of recognition sites and the cellular mechanisms responsible for the effects produced by -site ligands have not been clearly determined, although these compounds may act as neuromodulators. Previous reports have associated -site ligands with calcium homeostasis (Brent et al., 1996;Hayashi et al., 2000;Hayashi and Su, 2001). -site ligands can influence [ 3 H]dopamine and [ 3 H]norepinephrine (NE) release from rat brain slices, acting, at least partially, presynaptically (Gonzalez-Alvear and Werling, 1995;Gonzalez and Werling, 1997).Several -site ligands influence electrically evoked contractions in the guinea pig longitudinal muscle/myenteric plexus preparation (Campbell et al., 1989). These latter findings add evidence to the theory that recognition sites participate in the regulation of autonomic functions and that -site ligands may interfere with neurotransmitter release, modulating their action on innervated tissue (Su and J...

show abstract

Intrasynaptosomal free calcium levels in rat forebrain synaptosomes: modulation by sigma (σ) receptor ligands

Cited by 15 publications

References 12 publications

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

A Presynaptic Action of the Neurosteroid Pregnenolone Sulfate on GABAergic Synaptic Transmission

Ocular Hypotensive Action of Topical Flunarizine in the Rabbit: Role of ς₁Recognition Sites

Contact Info

Product

Resources

About

Intrasynaptosomal free calcium levels in rat forebrain synaptosomes: modulation by sigma (σ) receptor ligands

Cited by 15 publications

References 12 publications

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

Neurosteroids Enhance Spontaneous Glutamate Release in Hippocampal Neurons

A Presynaptic Action of the Neurosteroid Pregnenolone Sulfate on GABAergic Synaptic Transmission

Ocular Hypotensive Action of Topical Flunarizine in the Rabbit: Role of ς1Recognition Sites

Contact Info

Product

Resources

About

Ocular Hypotensive Action of Topical Flunarizine in the Rabbit: Role of ς₁Recognition Sites