Wednesday, February 5, 2025
2/5/2025
Mechanism of dual NaV1.7 and NaV1.8 block by a NaV inhibitory peptide aptamer Summary/Abstract: Multiple sensory neuronal sodium channels (NaVs) contribute to pain pathogenesis, indicating that development of a strategy for specific block of multiple NaVs in the pathological sensory neurons would be more effective for inhibiting pain signals than inhibiting only single NaV subtype. We discovered a polyacidic peptide from NaV1.7 intracellular segment and voltage-clamp recording shows that this peptide potently inhibits sodium currents conducted by both NaV1.7 and NaV1.8 (NaV1.7/1.8) channels. This dual NaV1.7/1.8 inhibitory peptide aptamer (named 1.7/1.8iPA, 38mer) contains a conserved Ankyrin (AnkG) binding domain and a multi-PDZ-domain protein class I binding domain (Pdzd2-I) between NaV1.7 and NaV1.8, suggesting that either AnkG or Pdzd2-I domain or both within 1.7/1.8iPA may contribute to its dual NaV1.7/1.8 inhibition. The overall goal of this proposal is to investigate 1) whether AnkG and/or Pdzd2-I domains in 1.7/1.8iPA is responsible for its dual NaV1.7/1.8 inhibition, and 2) whether expression of sequence defined 1.7/1.8iPA in the primary sensory neurons (PSN) will suppress PSN excitability, supporting 1.7/1.8iPA as a potential analgesic lead. Two specific aims will be investigated to test the hypothesis that 1.7/1.8iPA elicits dual block of NaV1.7/1.8 currents via a combined effects of AnkG and Pdzd2-I domains, leading to suppression of PSN action potential firing. Specific aim 1 will investigate and determine ion channel selectivity of 1.7/1.8iPA by in vitro of cell-based voltage-clamp recordings using HEK cells stably expressing various NaV subtypes and NG108-15 neuronal cells that naturally express potassium channels KV7.2/7.3 (both containing conserved AnkG binding domain). Specific aim 2 will determine electrogenesis and biological activity (neurotoxicity and animal behaviors) of 1.7/1.8iPA expression in the rat PSNs. Successful completion of this application will provide sufficient data to determine whether 1.7/1.8iPA is a potential analgesic lead to be further developed for AAV- mediated, PSN-specific dual NaV1.7/1.8 inhibition to treat chronic pain.
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