Inhibition of rat brain adenylate cyclase activity by benzodiazepine through the effects on Gi and catalytic proteins

Dan'ura, Toshio; Kurokáwa, Tomonori; Yamashita, Atsushi; Yanagiuchi, Hidemi; Ishibashi, Shun

doi:10.1016/0024-3205(88)90086-0

Cited by 17 publications

(16 citation statements)

References 20 publications

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“…In contrast, the extremely steep and nearly linear secondary phase of inhibition observed with micromolar amounts of BZs supports earlier evidence that high concentrations of these drugs can act directly on the AC enzyme (Dan'ura et al, 1988 Figure 4. The fact that the central-type BZ antagonist, flumazenil, failed to block the inhibitory effects of Ro5-4864 on AC activity in this study, as well as that of diazepam in previous studies (Dan'ura et al, 1988;Niles & Hashemi, 1990), indicates that it is inactive at the Gi-coupled BZ receptor. In contrast to flumazenil, the peripheral-type BZ receptor ligand, PK 11 195, blocked the first phase of inhibition by Ro5-4864, suggesting involvement of a receptor with PBR-like pharmacological characteristics.…”

Section: Discussionsupporting

confidence: 87%

“…Both the binding and functional data suggest that a high (nanomolar)-affinity Gi-coupled BZ receptor mediates inhibitory signalling via the AC pathway by BZ agonists. This is in contrast to the micromolar affinity site described by Dan'ura et al (1988). However, this discrepancy could involve tissue differences as their studies were carried out in rat whole brain preparations while striatal tissues were utilized in this study.…”

Section: Discussionmentioning

confidence: 81%

“…Recent studies have suggested the presence of another BZ receptor which is coupled to an inhibitory guanine nucleotide binding protein (Gi) in the central nervous system (CNS) (Dan'ura, 1988;Niles & Hashemi, 1990). Dan'ura et al (1988) found that micromolar concentrations of diazepam could inhibit adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] (AC) activity in rat whole brain and this effect could be inhibited by pertussis toxin.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Dan'ura et al (1988) found that micromolar concentrations of diazepam could inhibit adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] (AC) activity in rat whole brain and this effect could be inhibited by pertussis toxin. Furthermore, Rol 5-1788 (flumazenil), a central-type BZ receptor antagonist, had no effect on AC activity or on its inhibition by diazepam (Dan'ura et al, 1988). This finding was later confirmed by Niles & Hashemi (1990) who also found that flumazenil failed to block the inhibition of forskolin-stimulated AC activity by and pharmacological concentrations of the indoleamine hormone, melatonin, in the rat striatum.…”

Section: Introductionmentioning

confidence: 99%

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PK 11195 blockade of benzodiazepine‐induced inhibition of forskolin‐stimulated adenylate cyclase activity in the striatum

Tenn

Neu

Niles

1996

British J Pharmacology

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1 The effects of benzodiazepine receptor antagonists on the inhibition of forskolin-stimulated adenylate cyclase (AC) activity by various benzodiazepine (BZ) and indoleamine agonists in the rat striatum were investigated. 2 A biphasic inhibition of forskolin-stimulated AC activity by the peripheral-type agonist, Ro5-4864, and a multiphasic inhibition by the non-selective BZ, diazepam, was observed. One phase of AC inhibition is consistent with a Gi-coupled receptor-mediated action, whereas the other phases appear to involve a direct effect on the enzyme itself. 3 While the central-type antagonist, flumazenil, had no effect on the ability of Ro5-4864 to inhibit AC activity, the peripheral-type receptor ligand, PK 11195, abolished the first phase of inhibition. 4 PK 11195 and pertussis toxin were found to block the inhibitory effect of various BZs and the indoleamines, melatonin and 2-iodomelatonin, on induced AC activity. 5 Saturation binding studies, conducted at 30'C with [3H]-diazepam revealed a single binding site in the rat striatum (KD = 19.3 + 0.80 nM) which significantly decreased in affinity in the presence of GTP (KD = 30.5+2.6 nM; P<0.05). No significant change in B,,,, was observed. 6 These findings indicate the presence of G,-coupled BZ receptors in the rat striatum. Thus, suppression of cyclic AMP production may contribute to the diverse neuropharmacological effects of BZs, melatonin and related drugs.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

PK 11195 blockade of benzodiazepine‐induced inhibition of forskolin‐stimulated adenylate cyclase activity in the striatum

Tenn

Neu

Niles

1996

British J Pharmacology

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Phenotypic insights into ADCY5 ‐associated disease

et al. 2016

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BackgroundAdenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal‐dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations.MethodsIn 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole‐exome sequencing.ResultsFive patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile‐onset action‐induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement.ConclusionWe further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5‐associated dyskinesia may be under‐recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

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Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

Abela¹,

Kurian²

2018

J of Inher Metab Disea

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Movement disorders comprise a group of heterogeneous diseases with often complex clinical phenotypes. Overlapping symptoms and a lack of diagnostic biomarkers may hamper making a definitive diagnosis. Next-generation sequencing techniques have substantially contributed to unraveling genetic etiologies underlying movement disorders and thereby improved diagnoses. Defects in dopaminergic signaling in postsynaptic striatal medium spiny neurons are emerging as a pathogenic mechanism in a number of newly identified hyperkinetic movement disorders. Several of the causative genes encode components of the cAMP pathway, a critical postsynaptic signaling pathway in medium spiny neurons. Here, we review the clinical presentation, genetic findings, and disease mechanisms that characterize these genetic postsynaptic movement disorders.

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Inhibition of rat brain adenylate cyclase activity by benzodiazepine through the effects on Gi and catalytic proteins

Cited by 17 publications

References 20 publications

PK 11195 blockade of benzodiazepine‐induced inhibition of forskolin‐stimulated adenylate cyclase activity in the striatum

PK 11195 blockade of benzodiazepine‐induced inhibition of forskolin‐stimulated adenylate cyclase activity in the striatum

Phenotypic insights into ADCY5 ‐associated disease

Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

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