Takeda believes endosomal signaling for substance P could revive the pain target
With evidence mounting that cell surface receptors keep signaling after they are internalized, a Takeda-backed study from Monash University has shown how the phenomenon could solve the riddle of why antagonists of the substance P receptor failed as analgesics in the clinic, despite having shown so much preclinical promise. Using compounds that act only in the endosome, the partners want to lead the way in rethinking targeting of GPCRs to produce greater efficacy.
The findings could not only open the door to a new class of inhibitors for GPCRs, but also re-ignite interest in the pain target at a time when the need for non-opioid analgesics is gaining national attention.
The idea of endosomal signaling goes against the canonical GPCR model in which receptors on the plasma membrane respond to extracellular ligands, transmit intracellular signals by coupling to G proteins, and then terminate signaling by undergoing endocytosis which removes the receptors from the cell surface.
In that model, endosomes serve as a sorting station to receive internalized receptors, and then either recycle them to the membrane or send them to the lysosome to be destroyed.
Researchers have been chipping away at the cell surface-centric dogma for nearly 20 years, establishing the “signaling endosome” hypothesis to explain receptor signaling during endosome trafficking observed in cell culture data on GPCRs such as the β2 adrenergic receptor and TSHR, as well as tyrosine kinase receptors such as TrkA.
Now, in Science Translational Medicine, a