Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief.

ABSTRACT: The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for rational design of such compounds are ill-defined. Moreover, the role of natural GPCR variants, which exhibit aberrant signaling and endosomal trafficking, in maintaining pain is unknown. Herein, substance P (SP) was found to evoke clathrin-mediated assembly of endosomal signaling complexes comprising neurokinin 1 receptor (NK₁R), Gα_q/i, and βarrestin-2. Whereas the FDA-approved NK₁R antagonist aprepitant induced

SUBMITTER: Hegron A 

PROVIDER: S-EPMC10235985 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature