Characterization of the peptide derived from the PI3K anchoring site on TrkA and its effect on the signaling pathway.

• Grant number: 24/05278-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2024
• End date: May 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Deborah Schechtman
• Grantee: Giovanna Souza Stival
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/06982-6 - Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain, AP.TEM

Abstract

Currently, the search for effective treatments for pain relief is a significant challenge, as many individuals do not experience significant improvements when resorting to anti-inflammatory analgesics and/or opioids available in the market. To address this therapeutic gap, we must have a better understanding of the pathways leading to pain signaling, with particular interest in the pathway mediated by the tropomyosin receptor kinase A (TrkA), a tyrosine kinase activated upon binding to nerve growth factor (NGF). The formation of the TrkA-NGF complex acts on the phosphorylation of specific tyrosines, activating binding sites of TrkA's PTB and SH2 domains, which serve as anchoring sites for important pathways such as the mitogen-activated protein kinase (MAPK), the regulatory domain of phosphatidylinositol 3-kinase (PI3K), and phospholipase C (PLC). The first two activate the ERK cascade and Akt protein, which govern basic cellular processes such as cell proliferation/differentiation, signal duration/intensity, and neuron growth/survival. Lastly, when activated, the PLC pathway triggers the activation of protein kinase C (PKC) through calcium release into the cytoplasm, which is essential for phosphorylation of the Transient Receptor Potential Cation Channel (TRPV1), a vanilloid channel involved in multiple physiological processes beyond pain signaling. Studies conducted by our laboratory concluded that inhibiting the interaction between PLC and the dimerized TrkA receptor, using a peptide mimetic of TrkA's binding site to PLC's SH2 domain (TAT-pQYP), inhibited PLC interaction and activation, as well as mechanical nociception in an inflammatory model, demonstrating the importance of PLC stimulation for pain signal transmission. Therefore, this result further underscored the importance of studying the interaction between TrkA and its respective signaling pathways. Consequently, we aim to study the relationship between TrkA and PLC and PI3K proteins using the inhibitory peptides TAT-pQYP and TAT-pPI3K, respectively, aiding in the development of new, more effective non-opioid therapies with significant potential outcomes.