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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

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 K_i 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.

Address correspondence to: Dr. Phillip J. Robinson, Cell Signaling Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, Sydney, NSW 2145, Australia. E-mail: probinson{at}cmri.com.au