Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release
| Autor: | Jiafu Wang, Miaomiao Kong, Xiaolong Dai, Yu Dou, Yang Liu, Weiwei Chen, Shanghai Xue, Yanqing Li, Wanzhi Wang, Yinghao Zhang, Jianghui Meng |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Membrane Fusion Rats Sprague-Dawley Transient receptor potential channel Mice Pirt TAC1 cytokine Neurotoxin Botulinum Toxins Type A Biology (General) Receptor Spectroscopy G alpha subunit Chemistry Nociceptors dorsal root ganglia General Medicine gene therapy Computer Science Applications Cell biology SNARE Female chronic pain Neuropeptide Y receptor Y2 Sensory Receptor Cells Synaptosomal-Associated Protein 25 QH301-705.5 Transgene Neuropeptide Pain neuronal promoter Catalysis Article Inorganic Chemistry Peripheral Nervous System Animals Humans Physical and Theoretical Chemistry Molecular Biology neuropeptide QD1-999 Organic Chemistry Neuropeptides Membrane Proteins neurotoxin Rats Mice Inbred C57BL Animals Newborn |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 8826, p 8826 (2021) International Journal of Molecular Sciences Volume 22 Issue 16 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1 CALCB, calcitonin gene-related peptide 2 HTR3A, 5-hydroxytryptamine receptor 3A NPY2R, neuropeptide Y receptor Y2 GPR52, G protein-coupled receptor 52 SCN9A, sodium voltage-gated channel alpha subunit 9 TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief. |
| Databáze: | OpenAIRE |
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