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Vol. 15, Issue 4, 1871-1880, April 2004

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Inhibition of Membrane Tubule Formation and Trafficking by Isotetrandrine, an Antagonist of G-protein-regulated Phospholipase A₂ Enzymes

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 18483

Submitted September 10, 2003; Revised November 30, 2003; Accepted January 11, 2004
Monitoring Editor: Jennifer Lippincott-Schwartz

Previous studies have established a role for cytoplasmic phospholipase A₂ (PLA₂) activity in tubule-mediated retrograde trafficking between the Golgi complex and the endoplasmic reticulum (ER). However, little else is known about how membrane tubule formation is regulated. This study demonstrates that isotetrandrine (ITD), a biscoclaurine alkaloid known to inhibit PLA₂ enzyme activation by heterotrimeric G-proteins, effectively prevented brefeldin A (BFA)-induced tubule formation from the Golgi complex and retrograde trafficking to the ER. In addition, ITD inhibited BFA-stimulated tubule formation from the trans-Golgi network and endosomes. ITD inhibition of the BFA response was potent (IC₅₀ 10-20 µM) and rapid (complete inhibition with a 10-15-min preincubation). ITD also inhibited normal retrograde trafficking as revealed by the formation of nocodazole-induced Golgi mini-stacks at ER exit sites. Treatment of cells with ITD alone caused the normally interconnected Golgi ribbons to become fragmented and dilated, but cisternae were still stacked and located in a juxtanuclear position. These results suggest that a G-protein-binding PLA₂ enzyme plays a pivotal role in tubule mediated trafficking between the Golgi and the ER, the maintenance of the interconnected ribbons of Golgi stacks, and tubule formation from endosomes.

^* Corresponding author. E-mail address: wjb5{at}cornell.edu.

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