Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca 2+ Channel, Cav1.2, via pH i Increase and [Cl - ] i Decrease in the Lung Airway Epithelial Cells of Mice.

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 Ca 2+ channel (Ca V 1.2) and a small transient Ca 2+ release in the ciliated lung airway epithelial cells (c-LAECs) of mice. The activation of Ca V 1.2 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 + -HCO 3 - 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 Ca 2+ -free solution or nifedipine (an inhibitor of Ca V 1.2) inhibited 70% of the CBF and CBA enhancement using ABX, Ca V 1.2 enhanced most of the CBF and CBA increases using ABX. The activation of the Ca V 1.2 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.