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Sci Signal ; 15(731): eabm6046, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35471943

RESUMO

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the NTRK1 gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). NTRK1 encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase Cγ (PLCγ). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCγ. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCγ and decreased NGF-induced, TrkA-mediated PLCγ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.


Assuntos
Hipo-Hidrose , Mutação , Insensibilidade Congênita à Dor , Fosfolipase C gama , Receptor trkA , Analgésicos/farmacologia , Animais , Canalopatias/genética , Canalopatias/metabolismo , Células HEK293 , Humanos , Hipo-Hidrose/genética , Hipo-Hidrose/metabolismo , Camundongos , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/farmacologia , Dor/genética , Dor/metabolismo , Insensibilidade Congênita à Dor/genética , Insensibilidade Congênita à Dor/metabolismo , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo
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