2:45 PM
Jul 13, 2017
 |  BC Innovations  |  Targets & Mechanisms

Insider signaling

Takeda believes endosomal signaling for substance P could revive the pain target

Editor's Note: This article was updated on Jul 14, 2017 at 1:43 PM PDT

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 team led by Nigel Bunnett has produced the strongest case to date for a therapeutic relevance of endosomal GPCR signaling, showing blockade of endocytosis prevents pain signaling, and that internalized receptors largely account for the sustained substance P-mediated antinociceptive effect. When he led the study, Bunnett was a professor at Monash; he recently moved to Columbia University where he is a professor in the department of surgery

In addition, the team showed conjugation of specific lipids to inhibitors of the substance P receptor could target the molecules to the endosome and block the signal -- about 90%, as shown in some pain assays -- compared with about 10% for conventional antagonists that act on the plasma membrane receptor.

“The fundamental observation for me was that endocytosis is important for chronic pain,” said Gareth Hicks, VP & head of the gastrointestinal drug discovery unit at Takeda Pharmaceutical Co. Ltd., who co-authored the study.

He said Takeda is interested in the target for visceral pain and sees the results as more than only a validation of the endosomal signaling mechanism. “This could be the reason why NK1 receptor antagonists failed in chronic disease. This could be the answer, so we absolutely have to follow this up.”


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