Surfactant Effects of Chlorpromazine and Imipramine on Lipid Bilayers Containing Sphingomyelin and Cholesterol

Ahyayauch, Hasna; Requero, M. Asun; Alonso, Alicia; Bennouna, Mohammed; Goñi, Félix M.

doi:10.1006/jcis.2002.8690

Cited by 26 publications

(24 citation statements)

References 22 publications

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“…The MiTMAB series of compounds are surface-active, and they are predicted to alter protein-lipid interactions (Scurlock and Curtis, 1981;Schreier et al, 2000). At high concentrations [at, or exceeding, the critical micellar concentration (cmc); see Discussion)], these compounds are cationic surfactants, as observed for other pharmacologically active cationic amphiphilic compounds such as chlorpromazine or imipramine (Ahyayauch et al, 2002). Therefore, several approaches were used to determine whether MiTMAB targets the dynamin-phospholipid interaction.…”

Section: Resultsmentioning

confidence: 99%

“…Many drugs of clinical importance have nonionic or cationic amphiphilic properties (Fischer et al, 1998;Schreier et al, 2000;Ahyayauch et al, 2002). Studies into the molecular mechanisms of pharmacological effects exerted by drugs of such structure commonly reveal they have surface-active properties, such as self-aggregation and the ability to interact with membranes.…”

Section: Discussionmentioning

confidence: 99%

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Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Quan

McGeachie²,

Keating³

et al. 2007

Mol Pharmacol

113

141

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Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We developed a series of surface-active small-molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadecyltrimethyl ammonium bromide (OcTMAB), and we now show MiTMAB targets the dynamin-phospholipid interaction. MiT-MAB inhibited dynamin GTPase activity, with a K i of 940 Ϯ 25 nM. It potently inhibited receptor-mediated endocytosis (RME) of transferrin or epidermal growth factor (EGF) in a range of cells without blocking EGF binding, receptor number, or autophosphorylation. RME inhibition was rapidly reversed after washout. The rank order of potency for a variety of MiTMAB analogs on RME matched the rank order for dynamin inhibition, suggesting dynamin recruitment to the membrane is a primary cellular target. MiTMAB also inhibited synaptic vesicle endocytosis in rat brain nerve terminals (synaptosomes) without inducing depolarization or morphological defects. Therefore, the drug rapidly and reversibly blocks multiple forms of endocytosis with no acute cellular damage. The unique mechanism of action of MiTMAB provides an important tool to better understand dynamin-mediated membrane trafficking events in a variety of cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Quan

McGeachie²,

Keating³

et al. 2007

Mol Pharmacol

113

141

View full text Add to dashboard Cite

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“…Two additional tricyclic compounds, clozapine (13) and acriflavine (14), had minimal effect at 100 M (Fig. 5B), as did five cationic amphiphiles compounds that lack a tricyclic ring structure, including tetracaine (15), haloperidol (16), ifenprodil (17), U18666A (18), and diphenhydramine (19) (Fig. 5C).…”

Section: Resultsmentioning

confidence: 99%

“…To test the hypothesis that the conformation of mammalian SCAP might change in response to membrane properties, we tested the effects of chlorpromazine and imipramine, two prototypical cationic amphiphiles that are known to perturb membrane structure (10,(16)(17)(18). We asked whether these compounds might alter SCAP conformation in the in vitro trypsin digestion assay and whether the response to these drugs might be enhanced by Insig-1 coexpression.…”

Section: Resultsmentioning

confidence: 99%

Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles

Adams

Goldstein²,

Brown³

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…29,30) At high concentrations, MiTMAB is a cationic surfactant, as observed for other pharmacologically active cationic amphiphilic compounds, including chlorpromazine, an antipsychotic, and imipramine, an antidepressant. 31) Further, chlorpromazine is well known as an endocytosis inhibitor. 32) Thus, the inhibition of Dyn I GTPase activity by various psychotropic drugs was investigated to explore potentially clinically useful endocytosis inhibitors and to understand their mechanism of action.…”

mentioning

confidence: 99%

Some Selective Serotonin Reuptake Inhibitors Inhibit Dynamin I Guanosine Triphosphatase (GTPase)

Otomo

Takahashi

Mizumoto

et al. 2008

Biological & Pharmaceutical Bulletin

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Neuronal dynamin I plays a critical role in the recycling of synaptic vesicles, and thus in nervous system function. We expressed and purified dynamin I to explore potentially clinically useful endocytosis inhibitors and to examine the mechanism of their action. We estimated the IC 50 of nineteen psychotropic drugs for dynamin I. The IC 50 values of two selective serotonin reuptake inhibitors (sertraline and fluvoxamine) were 7.3؎1.0 and 14.7؎1.6 m mM, respectively. Kinetic analyses revealed that fluvoxamine is a noncompetitive inhibitor of dynamin I guanosine triphosphatase (GTPase) with respect to guanosine 5-triphosphate (GTP) and a competitive inhibitor with respect to L-phosphatidylserine (PS). Fluvoxamine may compete with PS for binding to the pleckstrin homology domain of dynamin I. On the other hand, sertraline was a mixed type inhibitor with respect to both GTP and PS. Our results indicate that sertraline and fluvoxamine may regulate the transportation of neurotransmitters by modulating synaptic vesicle endocytosis via the inhibition of dynamin I GTPase.

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Surfactant Effects of Chlorpromazine and Imipramine on Lipid Bilayers Containing Sphingomyelin and Cholesterol

Cited by 26 publications

References 22 publications

Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles

Some Selective Serotonin Reuptake Inhibitors Inhibit Dynamin I Guanosine Triphosphatase (GTPase)

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