PT  - JOURNAL ARTICLE
AU  - Annie Quan
AU  - Andrew B. McGeachie
AU  - Damien J. Keating
AU  - Ellen M. van Dam
AU  - Jenny Rusak
AU  - Ngoc Chau
AU  - Chandra S. Malladi
AU  - Chen Chen
AU  - Adam McCluskey
AU  - Michael A. Cousin
AU  - Phillip J. Robinson
TI  - 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
AID  - 10.1124/mol.107.034207
DP  - 2007 Dec 01
TA  - Molecular Pharmacology
PG  - 1425--1439
VI  - 72
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/72/6/1425.short
4100  - http://molpharm.aspetjournals.org/content/72/6/1425.full
SO  - Mol Pharmacol2007 Dec 01; 72
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics