Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase

A GPCR, the parathyroid hormone receptor, can elicit a sustained signal from internal membranes after internalization. The signal was found to be terminated by a feedback mechanism where PKA activates the proton pump v-ATPase, which acidifies endosomes. The PTH receptor is to our knowledge one of the first G protein–coupled receptor (GPCR) found to sustain cAMP signaling after internalization of the ligand–receptor complex in endosomes. This unexpected model is adding a new dimension on how we think about GPCR signaling, but its mechanism is incompletely understood. We report here that endosomal acidification mediated by the PKA action on the v-ATPase provides a negative feedback mechanism by which endosomal receptor signaling is turned off.