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J. Cell Biol., Volume 142, Number 1, July 13, 1998 25-38

PDMP Blocks Brefeldin A-induced Retrograde Membrane Transport from Golgi to ER: Evidence for Involvement of Calcium Homeostasis and Dissociation from Sphingolipid Metabolism

Jan Willem Kok,* Teresa Babia,§ Catalin M. Filipeanu,Dagger Adriaan Nelemans,Dagger Gustavo Egea,§ and Dick Hoekstra*

* Department of Physiological Chemistry, Dagger  Department of Clinical Pharmacology, University of Groningen, Groningen Institute for Drug Studies (GIDS), 9713 AV Groningen, The Netherlands; and § Universitat de Barcelona, Facultat de Medicina, Departament de Biologia Cellular, Institut d'Investigacions Biomediques August Pi I Sunyer, 08036 Barcelona, Spain

In this study, we show that an inhibitor of sphingolipid biosynthesis, D,L-threo-1-phenyl-2- decanoylamino-3-morpholino-1-propanol (PDMP), inhibits brefeldin A (BFA)-induced retrograde membrane transport from Golgi to endoplasmic reticulum (ER). If BFA treatment was combined with or preceded by PDMP administration to cells, disappearance of discrete Golgi structures did not occur. However, when BFA was allowed to exert its effect before PDMP addition, PDMP could not "rescue" the Golgi compartment.

Evidence is presented showing that this action of PDMP is indirect, which means that the direct target is not sphingolipid metabolism at the Golgi apparatus. A fluorescent analogue of PDMP, 6-(N-[7-nitro-2,1,3-benzoxadiazol-4-yl]amino)hexanoyl-PDMP (C6-NBD-PDMP), did not localize in the Golgi apparatus. Moreover, the effect of PDMP on membrane flow did not correlate with impaired C6-NBD-sphingomyelin biosynthesis and was not mimicked by exogenous C6-ceramide addition or counteracted by exogenous C6-glucosylceramide addition. On the other hand, the PDMP effect was mimicked by the multidrug resistance protein inhibitor MK571.

The effect of PDMP on membrane transport correlated with modulation of calcium homeostasis, which occurred in a similar concentration range. PDMP released calcium from at least two independent calcium stores and blocked calcium influx induced by either extracellular ATP or thapsigargin. Thus, the biological effects of PDMP revealed a relation between three important physiological processes of multidrug resistance, calcium homeostasis, and membrane flow in the ER/ Golgi system.

Key words: ceramide;  retrograde membrane flow;  beta -COP;  multidrug resistance;  intracellular calcium


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