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, Annie, McGeachie, Andrew B., Keating, Damien J., van Dam, Ellen M., Rusak, Jenny, Chau, Ngoc, Malladi, Chandra S., Chen, Chen, McCluskey, Adam, Cousin, Michael A. and Robinson, Phillip J. (2007) 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. Molecular Pharmacology, 72 6: 1425-1439. doi:10.1124/mol.107.034207


Author Quan, Annie
McGeachie, Andrew B.
Keating, Damien J.
van Dam, Ellen M.
Rusak, Jenny
Chau, Ngoc
Malladi, Chandra S.
Chen, Chen
McCluskey, Adam
Cousin, Michael A.
Robinson, Phillip J.
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
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
Publication date 2007-12-01
Year available 2007
Sub-type Article (original research)
DOI 10.1124/mol.107.034207
Open Access Status
Volume 72
Issue 6
Start page 1425
End page 1439
Total pages 15
Place of publication Bethesda MD
Publisher American Society for Pharamacology and Experimental Therapeutics
Language eng
Subject 110306 Endocrinology
110201 Cardiology (incl. Cardiovascular Diseases)
111201 Cancer Cell Biology
Abstract Cell Signalling Unit, Children's Medical Research Institute, University of Sydney, Sydney, Australia (A.Q., A.B.M., E.M.v.D., J.R., N.C., C.S.M., P.J.R.); Chemistry, School of Environmental and Life Sciences, University of Newcastle, Newcastle, Australia (A.M.); Department of Human Physiology, Flinders University, Adelaide, Australia (D.J.K.), Prince Henry's Institute of Medical Research, Victoria, Australia (C.C.); and, Membrane Biology Group, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Scotland (M.A.C) 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.
Keyword Pharmacology & Pharmacy
Pharmacology & Pharmacy
PHARMACOLOGY & PHARMACY
Q-Index Code C1
Grant ID 062841
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Biomedical Sciences Publications
 
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Created: Wed, 14 Jan 2009, 02:35:03 EST by Judy Dingwall on behalf of School of Biomedical Sciences