Botulinum Toxin Type A Inhibits Submandibular Secretion via the ERK/miR-124-3p/Specificity Protein 1/Claudin-1 Axis

Area of Science:

• Cell Biology
• Molecular Biology
• Gastroenterology

Background:

• Botulinum toxin type A (BTXA) treats sialorrhea, but its mechanism is unclear.
• Tight junctions (TJs), particularly claudin-1 (Cldn1), regulate salivary secretion via the paracellular pathway.
• Cldn1 acts as a barrier protein in salivary glands.

Purpose of the Study:

• To elucidate the molecular mechanism of BTXA in reducing salivary secretion.
• To investigate the role of tight junctions and related signaling pathways in BTXA's action.
• To identify the specific molecular axis involved in BTXA-mediated changes in paracellular permeability.

Main Methods:

• Upregulation of Cldn1 in BTXA-treated rat submandibular glands and SMG-C6 cells.
• Cldn1 knockdown to assess its role in paracellular permeability.
• Analysis of specificity protein-1 (Sp1) and ERK1/2 pathway involvement.
• Investigation of miR-124-3p targeting of Sp1 and its regulation by BTXA and ERK1/2.

Main Results:

• BTXA upregulated Cldn1 in submandibular glands and SMG-C6 cells.
• Cldn1 knockdown reversed BTXA-induced reduction in paracellular permeability.
• BTXA upregulated Sp1 via the ERK1/2 pathway, which was reversed by ERK1/2 inhibition.
• BTXA downregulated miR-124-3p, which targets Sp1; miR-124-3p overexpression counteracted Sp1 and Cldn1 upregulation.

Conclusions:

• BTXA reduces paracellular permeability in salivary glands.
• The mechanism involves the ERK1/2/miR-124-3p/Sp1/Cldn1 signaling axis.
• This pathway provides a molecular basis for BTXA's therapeutic effect in sialorrhea.