Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca²⁺ Channel, Cav1.2, via...

Ambroxol (ABX), a frequently prescribed secretolytic agent which enhances the ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of amplitude) by 30%, activates a voltage-dependent Ca²⁺ channel (Ca_V1.2) and a small transient Ca²⁺ release in the ciliated lung airway epithelial cells (c-LAECs) of mice. The activation of Ca_V1.2 alone enhanced the CBF and CBA by 20%, mediated by a pH_i increase_i and a [Cl^-]_i decrease in the c-LAECs. The increase in pH_i, which was induced by the activation of the Na⁺-HCO₃^- cotransporter (NBC), enhanced the CBF (by 30%) and CBA (by 15-20%), and a decrease in [Cl^-]_i, which was induced by the Cl^- release via anoctamine 1 (ANO1), enhanced the CBA (by 10-15%). While a Ca²⁺-free solution or nifedipine (an inhibitor of Ca_V1.2) inhibited 70% of the CBF and CBA enhancement using ABX, Ca_V1.2 enhanced most of the CBF and CBA increases using ABX. The activation of the Ca_V1.2 existing in the cilia stimulates the NBC to increase pH_i and ANO1 to decrease the [Cl^-]_i in the c-LAECs. In conclusion, the pH_i increase and the [Cl^-]_i decrease enhanced the CBF and CBA in the ABX-stimulated c-LAECs.