title: 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.
abstract: 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. MiTMAB inhibited dynamin GTPase activity, with a Ki of 940 +/- 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.
authors: Cell Signaling Unit, Children's Medical Research Institute, University of Sydney, Sydney, NSW 2145, Australia.
authors: Annie
authors: A
authors: Quan
authors: Andrew B
authors: AB
authors: McGeachie
authors: Damien J
authors: DJ
authors: Keating
authors: Ellen M
authors: EM
authors: van Dam
authors: Jenny
authors: J
authors: Rusak
authors: Ngoc
authors: N
authors: Chau
authors: Chandra S
authors: CS
authors: Malladi
authors: Chen
authors: C
authors: Chen
authors: Adam
authors: A
authors: McCluskey
authors: Michael A
authors: MA
authors: Cousin
authors: Phillip J
authors: PJ
authors: Robinson
mesh_terms: D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D034284:Dynamin I / Q000037:antagonists & inhibitors* / Q000502:physiology; D034285:Dynamin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology; D050337:Trimethyl Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000473:Alkanes; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; D050337:Trimethyl Ammonium Compounds; C518260:octadecyltrimethylammonium bromide; D034284:Dynamin I; D034285:Dynamin II; C009410:tetradecyltrimethylammonium