A Novel Catalytically Inactive Construct of Botulinum Neurotoxin A (BoNT/A) Directly Inhibits Visceral Sensory Signalling.

Autor: Ibrahim H; School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston Campus, Preston PR1 2HE, UK.; Ipsen, Abingdon OX14 4RY, UK., Retailleau K; Ipsen, 5 av Canada, 91940 Les Ulis, France., Hornby F; Ipsen, Abingdon OX14 4RY, UK., Maignel J; Ipsen, 5 av Canada, 91940 Les Ulis, France., Beard M; Ipsen, Abingdon OX14 4RY, UK., Daly DM; School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston Campus, Preston PR1 2HE, UK.
Jazyk: angličtina
Zdroj: Toxins [Toxins (Basel)] 2024 Jan 07; Vol. 16 (1). Date of Electronic Publication: 2024 Jan 07.
DOI: 10.3390/toxins16010030
Abstrakt: Botulinum neurotoxin A (BoNT/A) is a potent neurotoxin that silences cholinergic neurotransmission through the cleavage of the synaptic protein SNAP-25. Previous studies have shown that, in addition to its paralytic effects, BoNT/A can inhibit sensory nerve activity. The aim of this study was to identify how BoNT/A inhibits afferent signalling from the bladder. To investigate the role of SNAP-25 cleavage in the previously reported BoNT/A-dependent inhibition of sensory signalling, we developed a recombinant form of BoNT/A with an inactive light chain, rBoNT/A (0), unable to paralyse muscle. We also developed recombinant light chain (LC)-domain-only proteins to better understand the entry mechanisms, as the heavy chain (HC) of the protein is responsible for the internalisation of the light chain. We found that, despite a lack of catalytic activity, rBoNT/A (0) potently inhibited the afferent responses to bladder distension to a greater degree than catalytically active rBoNT/A. This was also clear from the testing of the LC-only proteins, as the inactive rLC/A (0) protein inhibited afferent responses significantly more than the active rLC/A protein. Immunohistochemistry for cleaved SNAP-25 was negative, and purinergic and nitrergic antagonists partially and totally reversed the sensory inhibition, respectively. These data suggest that the BoNT/A inhibition of sensory nerve activity in this assay is not due to the classical well-characterised 'double-receptor' mechanism of BoNT/A, is independent of SNAP25 cleavage and involves nitrergic and purinergic signalling mechanisms.
Databáze: MEDLINE
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