EXPRESSION OF DROSOPHILA-MELANOGASTER P-GLYCOPROTEINS IS ASSOCIATED WITH ATP CHANNEL ACTIVITY

Two distinct Drosophila melanogaster P-glycoprotein (Pgp) gene homolog ues of different chromosomal origin, MDR49 and MDR65, have been previo usly identified (38). Most Pgps are implicated in the development of t he multidrug-resistance phenotype. Despite intense efforts to identify the molecular mechanism(s) associated with Pgp function, the endogeno us substrate(s) of these transport molecules is largely unknown. Recen t studies from our laboratory indicate that a murine Pgp homologue (E. H. Abraham, A. G. Prat, L. Gerweck, T. Seneveratne, R. J. Arceci, R. Kramer, G. Guidotti, and H. F. Cantiello. Proc. Natl. Acad. Sci. USA 9 0: 312-316, 1993) and a related protein, the cystic fibrosis transmemb rane conductance regulator (CFTR; I. L. Reisin, A. Prat, E. H. Abraham , J. F. Amara, R. J. Gregory, D. A. Ausiello, and H. F. Cantiello. J. Biol. Chem. 269: 20584-20591, 1994), are novel ATP-permeable ion chann els. The common feature of these two proteins is the conserved ATP-bin ding cassettes (ABC); thus molecules structurally linked to the ABC tr ansporter family may be also functionally associated with ATP channel activity. In this study, MDR65 and MDR49 Pgps were functionally expres sed in Sig cells, and patch-clamp techniques were applied to assess th e role of these proteins in the electrodiffusional movement of ATP. In the presence of intracellular ATP and external NaCl, expression of MD R65 was associated with a linear electrodiffusional pathway that was p ermeable to both ATP and Cl-. Under symmetrical ATP conditions, only v oltage depolarization activated a MDR65-mediated ATP-conductive pathwa y. Expression of MDR49 was also associated with a voltage-activated AT P conductance in symmetrical ATP, but no apparent permeability to eith er Cl- or ATP was observed under asymmetrical conditions. The differen t functional properties of MDR65 and MDR49 may be indicative of distin ct physiological roles in this organism. The study indicates, however, that the two Drosophila Pgp homologues share strong functional simila rities with their mammalian relatives Pgp and CFTR.