Peptides derived from the human transferrin receptor stimulate endosomal acidification via a G(i)-type protein

Background. Acidification of the endosomal compartment is a prerequisite fo r intracellular processing of endocytosed complexes. Endosomal acidificatio n is accomplished by an H+-ATPase, in parallel with a Cl- conductance. Prev ious studies from our laboratory have demonstrated that endosomal acidifica tion is modulated by a pertussis toxin-sensitive mechanism, suggesting that endosomal acidification could be regulated through a self-contained signal transduction pathway. This study was designed to test this hypothesis usin g the transferrin receptor as a model. Methods. Synthetic peptides corresponding to a region of the cytosolic doma in of the transferrin receptor and containing a KPKR sequence were used to stimulate endosomal acidification in a G-protein-dependent manner. Results. Peptides activated the G(i), as evidenced by stimulation of the ra te of GTP gamma S binding. A transferrin receptor peptide that lacked the K PKR sequence did not stimulate endosomal acidification and failed to promot e GTP gamma S binding to Gi proteins. Conclusions. These results demonstrate that regulation of endosomal acidifi cation can be achieved, in part, through a G(i)-mediated signal transductio n pathway. These findings suggest that regulation of endosomal acidificatio n through such a pathway may facilitate intracellular processing of the tra nsferrin receptor.