Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations.

Taft, William C.; DeLorenzo, Robert J.

doi:10.1073/pnas.81.10.3118

Cited by 99 publications

(33 citation statements)

References 29 publications

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“…High K+ produced membrane depolarization and an increase in 45Ca2+ uptake, as shown in figure 1. These kinetic profiles are consistent with those reported in earlier studies on 45Ca2+ uptake in similar brain synaptosomes [27][28][29][30], Preincubation with corticosterone (1 pM ) was without effect on the uptake under the resting (low K+) condition. However, in K+-depolarized synaptosomes, steroid prein cubation resulted in a marked stimulation of the uptake (40-45% above control).…”

Section: Corticosterone Effect On 45ca2+ Uptakesupporting

confidence: 81%

Glucocorticoid Action on Depolarization-Dependent Calcium Influx in Brain Synaptosomes

Sze

Iqbal²

1994

Neuroendocrinology

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Synaptic plasma membranes from the brain are known to have specific binding sites for several steroid hormones, but the mechanism of membrane trans-duction of steroid signals is not understood. In this study, corticosterone was found to stimulate ⁴⁵Ca²⁺ uptake in brain synaptosomes upon depolarization of the synaptosomes by high K⁺ (70 mM). The stimulation of the depolarization-dependent ⁴⁵Ca²⁺ uptake by corticosterone is concentration dependent, with the maximal effect occurring at steroid concentration of 5 – 10 × 10^–7M (70–80% above control). The EC₅₀ is estimated as 1.3 × 10^–7M, which is almost identical to the K_dof the specific binding of the steroid to synaptic membranes (1.2 × 10^–7M) reported previously. The stimulation of ⁴⁵Ca²⁺ uptake in brain synaptosomes is specific to corticosterone and other glucocorticoids (cortisol, dexamethasone and triamcinolone); gonadal steroids (17β-estradiol, progesterone and testosterone) are ineffective. [³H]Nitrendipine binding was used to examine the effect of corticosterone on voltage-dependent Ca²⁺ channels. No effect on [³H]nitrendipine binding was found when disrupted synaptic membranes were preincubated with the steroid. However, a significant increase of membrane binding of [³H]nitrendipine was found when intact synaptosomes were first preincubated with the steroid at 37°C and then disrupted. Steroid preincubation of synaptosomes at 0°C was ineffective. Since preincubation at 37°C is required, it appears that metabolic processes modulating Ca²⁺ channel activity are involved in the steroid action.

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Section: Corticosterone Effect On 45ca2+ Uptakesupporting

confidence: 81%

Glucocorticoid Action on Depolarization-Dependent Calcium Influx in Brain Synaptosomes

Sze

Iqbal²

1994

Neuroendocrinology

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“…22 It increases the frequency of chloride ion channel opening, enhancing the inhibitory effect of GABA at the GABAa receptor; 23 however, it has multiple other central effects. Benzodiazepines have also been shown to have an inhibitory effect on voltage-dependant calcium channels, 24 which may be relevant in the setting of the UBR4 genetic variant that we have described in this family. Exome sequencing provided the most economic and efficient method for variant screening because of the large number of candidate genes in the single disease locus identified.…”

Section: Discussionmentioning

confidence: 75%

A novel locus for episodic ataxia:UBR4 the likely candidate

et al. 2013

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Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca 2 þ protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca 2 þ control within neuronal cells highlights its potential for a role in this form of EA.

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“…In addition to their well characterized effects at GABA A receptors, benzodiazepines were reported previously to inhibit neuronal VGCC-mediated Ca 2ϩ flux (Taft and DeLorenzo, 1984;Reuveny et al, 1993;Ishizawa et al, 1997). Micromolar benzodiazepine binding sites were proposed to mediate benzodiazepine inhibition of depolarizationdependent Ca 2ϩ uptake into synaptosomes, suggesting that diazepam brain concentrations achieved during intravenous administration for status epilepticus (Ͼ10 M) may be sufficient to block L-type VGCCs (Taft and DeLorenzo, 1984).…”

Section: Benzodiazepine Effect On Voltage-gated Calcium Currents 881mentioning

confidence: 99%

“…Micromolar benzodiazepine binding sites were proposed to mediate benzodiazepine inhibition of depolarizationdependent Ca 2ϩ uptake into synaptosomes, suggesting that diazepam brain concentrations achieved during intravenous administration for status epilepticus (Ͼ10 M) may be sufficient to block L-type VGCCs (Taft and DeLorenzo, 1984). Both FZP (IC 50 ϭ 0.4 mM) and DZP (IC 50 ϭ 1.3 mM) had weak potency to inhibit [ 3 H]PN200-110 binding to DHP binding sites (Fig.…”

Section: Benzodiazepine Effect On Voltage-gated Calcium Currents 881mentioning

confidence: 99%

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Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

Kong¹,

Earl²,

Davis³

et al. 2008

J Pharmacol Exp Ther

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Signs of physical dependence as a consequence of long-term drug use and a moderate abuse liability limit benzodiazepine clinical usefulness. Growing evidence suggests a role for voltage-gated calcium channel (VGCC) regulation in mediating a range of chronic drug effects from drug withdrawal phenomena to dependence on a variety of drugs of abuse. High voltageactivated (HVA) calcium currents were measured in whole-cell recordings from acutely isolated hippocampal CA1 neurons after a 1-week flurazepam (FZP) treatment that results in withdrawal-anxiety. An ϳ1.8-fold increase in Ca 2ϩ current density was detected immediately after and up to 2 days but not 3 or 4 days after drug withdrawal. Current density was unchanged after acute desalkyl-FZP treatment. A significant negative shift of the half-maximal potential of activation of HVA currents was also observed but steady-state inactivation remained unchanged. FZP and diazepam showed use-and concentration-

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Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations.

Cited by 99 publications

References 29 publications

Glucocorticoid Action on Depolarization-Dependent Calcium Influx in Brain Synaptosomes

Glucocorticoid Action on Depolarization-Dependent Calcium Influx in Brain Synaptosomes

A novel locus for episodic ataxia:UBR4 the likely candidate

Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

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