Paradoxical facilitation of exocytosis by inhibition of L-type calcium channels of bovine chromaffin cells

Rosa, Juliana M.; Conde, Marina; Nanclares, Carmen; Orozco, Angela; Colmena, Inés; Pascual, Ricardo de; Garcı́a, Antonio G.; Gandı́a, Luis

doi:10.1016/j.bbrc.2011.05.138

Cited by 8 publications

(10 citation statements)

References 32 publications

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“…The importance of appreciating off‐target drug action is further illustrated with our observation that calmidazolium and flunarizine are potent dynamin inhibitors. The widely used cationic amphipathic compound calmidazolium is a known potent inhibitor of calmodulin and endocytosis that has been previously used to show the role of calmodulin in SVE . However, our finding that calmidazolium potently inhibits dynamin I and II GTPase activity challenges this proposed role of calmodulin in SVE.…”

Section: Discussionmentioning

confidence: 69%

Phenothiazine‐Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin‐Mediated Endocytosis

Daniel

Chau

Abdel-Hamid

et al. 2015

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Chlorpromazine is a phenothiazine-derived antipsychotic drug (APD) that inhibits clathrin-mediated endocytosis (CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I (dynI) in the 2-12 μM range, the most potent being trifluoperazine (IC 50 2.6 ± 0.7 μM). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8-to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin.Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.

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Section: Discussionmentioning

confidence: 69%

Phenothiazine‐Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin‐Mediated Endocytosis

Daniel

Chau

Abdel-Hamid

et al. 2015

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“…At low blocker concentrations, it is plausible that the component of signalling pathways is stronger enough to overcome the effect of mild VACC inhibition. Also, in results from our lab performed in bovine adrenal chromaffin cells (secretory response activity) we clearly see this phenomenon: nifedipine enhances their secretory activity [9]. In addition, it is plausible that the biphasic effect of BAY K 8644 on neurogenic contraction (dose-dependent contraction and relaxation) [59] and secretion [60] could also be explained in the context of the "calcium paradox".…”

Section: A Calcium Paradox In the Context Of Neurotransmissionmentioning

confidence: 82%

“…For instance, in a study performed in voltage-clamped bovine chromaffin cells, the blockade of L channels with nifedipine transformed the exocytotic responses elicited by a double-pulse protocol, from depression to facilitation [9]. In an earlier study, it was shown that nifedipine suppressed the endocytotic response triggered by a long depolarising stimulus [17].…”

Section: Paradoxical Effects Of L Channel Blockers In Adrenal Chromafmentioning

confidence: 99%

“…An additional explanation for the nifedipine paradoxical effect in chromaffin cells [9] could be found in the context of the calcium paradox described in the vas deferens and in the interaction Ca 2+ -cAMP [10].…”

Section: Paradoxical Effects Of L Channel Blockers In Adrenal Chromafmentioning

confidence: 99%

“…However, near four decades ago verapamil at low concentrations was shown to unexpectedly augment the neurogenically mediated contractions of the rat vas deferens [8]. On the other hand, nifedipine was recently found to paradoxically augment the exocytotic release of catecholamine triggered by double-pulse depolarisations in voltage-clamped bovine adrenal medullary chromaffin cells [9]. How these two blockers of the L-subtype of VACCs can augment, instead of reducing the Ca 2+ -dependent responses of contraction and secretion?…”

Section: Introductionmentioning

confidence: 99%

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A Calcium Paradox in the Context of Neurotransmission

Bergantin¹,

Jurkiewicz²,

Garcı́a³

et al. 2015

JPP

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Abstract:The hypothesis of the calcium paradox has its origin in experiments done in neurogenically stimulated rat and mouse vas deferentia. Some old studies reported that reduction of Ca 2+ entry by mild concentrations of verapamil, diltiazem or nifedipine elicited the surprising augmentation of vas deferens contractions. Recent reports have also found that nifedipine caused a paradoxical augmentation of the exocytotic release of catecholamine elicited by paired depolarising pulses in voltage-clamped bovine chromaffin cells. Because these drugs are blocking the L-subtype of VACCs (voltage-activated calcium channels), augmented contraction and exocytosis was an unexpected outcome. Recent experiments in neurogenically-stimulated rat vas deferens have found a more drastic potentiation of contractions with the association of verapamil and cAMP-enhancer compounds. Thus, the interaction between the signalling pathways mediated by Ca 2+ and cAMP could explain those unexpected findings and the so-called calcium paradox.

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Single‐Vesicle Electrochemistry Reveals Sex Difference in Vesicular Storage and Release of Catecholamine

et al. 2022

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Quantitative measurements of sex difference in vesicle chemistry (i.e., chemical storage and release) at the single-vesicle level are essential to understand sex differences in cognitive behaviors; however, such measurements are very challenging to conventional analytical methods. By using single-vesicle electrochemistry, we find the duration of single exocytotic events of chromaffin cells prepared from male rats is statistically longer than that from female rats, leading to more neurotransmitter released in the male group. Further analysis reveals that a higher percentage of vesicles in the female group release part of the neurotransmitter, i.e., partial release, during exocytosis than that in male group. This sex dimorphism in neurotransmitter release in exocytosis might relate to the sex difference in the expression of voltage-dependent calcium channels and membrane lipid composition. Our finding offers the first experimental evidence that sex dimorphism even exists in vesicle chemistry, providing a brand new viewpoint for understanding the sex dimorphism in exocytosis.

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Paradoxical facilitation of exocytosis by inhibition of L-type calcium channels of bovine chromaffin cells

Cited by 8 publications

References 32 publications

Phenothiazine‐Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin‐Mediated Endocytosis

Phenothiazine‐Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin‐Mediated Endocytosis

A Calcium Paradox in the Context of Neurotransmission

Single‐Vesicle Electrochemistry Reveals Sex Difference in Vesicular Storage and Release of Catecholamine

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