Calcium and chlorpromazine interactions in rat synaptic plasma membranes

Breton, Joël; Viret, Jacques; Leterrier, F

doi:10.1016/0003-9861(77)90151-5

Cited by 31 publications

(11 citation statements)

References 35 publications

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“…It has been postulated that phenothiazines may inhibit exocytosis by displacing membranebound Ca (Liillmann et al 1980, Thaw et al 1982. By increasing the extracellular concentration of Ca2+, which competes with and displaces phenothiazines from membrane binding sites (Breton et al 1977), we found that the inhibitory effect of 30 ,UM trifluoperazine on hormone release from the GH, cells was counteracted.…”

Section: Discussionmentioning

confidence: 87%

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH₃ pituitary cells

Sletholt

Haug²,

Gordeladze

et al. 1987

Acta Physiologica Scandinavica

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In GH3 cells the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-napthalene sulphonamide hydrochloride (W-7) showed a dose-dependent, biphasic effect on the release of growth hormone (GH) and prolactin (PRL). Hormone release was inhibited with 15-30 microM trifluoperazine and with 30-80 microM W-7, while stimulation was observed with 50-100 microM trifluoperazine and with 150 microM W-7. Trifluoperazine (greater than or equal to 30 microM) and W-7 (greater than or equal to 80 microM) increased the concentration of cellular cyclic AMP. Sulphoxides of trifluoperazine and chlorpromazine (less than or equal to 150 microM were without effect on hormone release and cellular cyclic AMP. Hydrolysis of cyclic AMP by GH3 cytosol was reduced after incubation of intact GH3 cells with trifluoperazine (15-60 microM). When trifluoperazine was incubated with cytosol, both the high and low affinity forms of cyclic AMP phosphodiesterase were inhibited competitively with calculated Ki of 4.5 and 56 microM, respectively. Stimulation of cyclic AMP phosphodiesterase caused by endogenous calmodulin was blocked by trifluoperazine. Particulate bound adenylyl cyclase activity was inhibited by trifluoperazine, and this effect was counteracted by endogenous calmodulin.

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Section: Discussionmentioning

confidence: 87%

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH₃ pituitary cells

Sletholt

Haug²,

Gordeladze

et al. 1987

Acta Physiologica Scandinavica

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“…Indeed, such an action has been postulated to account for phenothiazine-induced inhibition of membrane fusion reactions including exocytosis (Poste & Allison, 1973). If this were so then it would be expected that the inhibition should be overcome by increasing the concentration of Ca which competes with and displaces phenothiazines from membrane-binding sites (Breton, Viret & Leterrier, 1977). However, increasing the Ca concentration 5or 10-fold did not reduce the inhibitory effect of the phenothiazines on A23187-induced secretion.…”

Section: Inhibition Of Exocytosis By Neuroleptic Drugsmentioning

confidence: 99%

On the calcium receptor activating exocytosis: inhibitory effects of calmodulin‐interacting drugs on rat mast cells.

Douglas¹,

Nemeth²

1982

The Journal of Physiology

111

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SUMMARY1. A series of neuroleptic drugs (five phenothiazines, imipramine, and pimozide) and the smooth muscle relaxant W-7, which all inhibit calcium-calmodulin-activated processes, inhibited rat mast cell secretion elicited by antigen, by 48/80, and by the calcium ionophore A23187.2. Neither the phenothiazines nor W-7 reduced 45Ca uptake in response to A23187. The drugs thus exert an inhibitory action distal to the rise in intracellular Ca ions that activates exocytosis.3. Chlorpromazine sulphoxide, which shares several membrane-perturbing actions of the phenothiazines but is a weak inhibitor of calmodulin, did not inhibit secretion. Moreover, the inhibitory effects of the phenothiazines were not overcome by a 5-or 10-fold increase in the concentration of calcium, which should counter unspecific membrane effects.4. The inhibitory effects of the various neuroleptic drugs appeared to be related to their ability to inhibit calmodulin because the individual potencies of these compounds on secretion evoked by 48/80 or A23187 correlated significantly with their reported potencies in inhibiting calmodulin-activated processes. (The greater potency and different rank order of these compounds on secretion evoked by antigen suggests an additional inhibitory action, perhaps involving Ca entry.) 5. These results, which parallel those obtained with drugs of this sort in smooth muscle where calmodulin seemingly functions as the Ca receptor activating contraction, strengthen the view that calmodulin, or some calmodulin-like protein, is the Ca receptor activating exocytosis.

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“…Alternatively, the inhibition of DNA repair could also be brought about by gross disorganisation of the membrane at high drug concentrations. In fact, it is known (Breton et al 1977) that in the low concentration range CPZ is located at the proteolipidic interface of the membrane but it penetrated deeper into the lipid structure at high concentrations leading to membrane denaturation and rigidification. The absence of radioprotective effect unter such conditions may therefore not be surprising.…”

Section: Resultsmentioning

confidence: 97%

Radioprotection of euoxic bacteria by phenothiazine drugs

Maniar

Nair

Singh

1984

Radiat Environ Biophys

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Survival studies on irradiated euoxic E. coli B/r cells in presence of various concentrations of four radioprotecting phenothiazine drugs have been carried out. Maximum radioprotection was obtained at a optimal concentration for each drug and it decreased on either side of it. The DNA strand break studies at the maximum protective and non-protective concentrations of chlorpromazine and promethazine revealed that the number of ssbs in DNA were less at the protective concentration which were efficiently repaired by the type-III repair process. On the other hand, at the non-protective concentrations, inhibition of DNA repair was noticed and a higher number of DNA ssbs were detected. We suggest that the membrane is fluidized to a greater extent at the protective concentrations allowing the chemical restitution of damaged sites by NPSH compounds. At the non-protective high concentrations of the drugs, the membrane may be too grossly disorganised to allow any repair and at the same time high concentrations of the drugs or their radicals may also react with radioprotective intracellular sulphhydryls.

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Calcium and chlorpromazine interactions in rat synaptic plasma membranes

Cited by 31 publications

References 35 publications

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH₃ pituitary cells

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH₃ pituitary cells

On the calcium receptor activating exocytosis: inhibitory effects of calmodulin‐interacting drugs on rat mast cells.

Radioprotection of euoxic bacteria by phenothiazine drugs

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Calcium and chlorpromazine interactions in rat synaptic plasma membranes

Cited by 31 publications

References 35 publications

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH3 pituitary cells

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH3 pituitary cells

On the calcium receptor activating exocytosis: inhibitory effects of calmodulin‐interacting drugs on rat mast cells.

Radioprotection of euoxic bacteria by phenothiazine drugs

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Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH₃ pituitary cells

Effects of calmodulin antagonists on hormone release and cyclic AMP levels in GH₃ pituitary cells