Figure 7. Schematic showing the proposed model for degradation of cell surface P-gp.

The half-life of cell surface P-gp (depicted in cyan color) is significantly long (25-27 h). The recycling of cell surface P-gp from early endosomes or other vesicles was not studied. Treatment with BafA1 or ammonium chloride that blocks acidification of acidic organelles extends the half-life of P-gp at the cell surface. The treatment with only proteasomal inhibitors including MG132, MG115, lactacystin or PSI has no effect on P-gp half-life at the cell surface suggesting that the proteasomal pathway may not be involved in degradation of cell surface P-gp. However, a combination treatment with proteasomal inhibitor MG132 along with the lysosomal inhibitor BafA1 resulted in prolonged P-gp retention time (increased half-life) at the cell surface, indicating that the proteasomal pathway becomes operative when the lysosomal pathway is blocked. The localization of P-gp to lysosomes, but not to early endosomes at steady-state indicates that lysosomal pathway plays a major role in the degradation of P-gp (BafA1 or ammonium chloride also inhibit endosomal acidification).