[Ca2+]i modulation of cAMP‐stimulated ciliary beat frequency via PDE1 in airway ciliary cells of mice

New Findings What is the central question of this study? The ciliary beat frequency (CBF) of the airway is controlled by [Ca2+]i. However, the effects of a reduction in [Ca2+]i on CBF are still controversial (an increase, a decrease or no change). What is the main finding and its importance? This study demonstrated that [Ca2+]i directly regulates CBF (direct action) and also indirectly regulates CBF via cAMP accumulation controlled by Ca2+‐dependent PDE1 activity (indirect action). The final CBF is determined by the balance of direct and indirect actions. PDE1 plays crucial roles in the regulation of airway CBF. [Ca2+]i plays crucial roles in the regulation of ciliary beat frequency (CBF) and ciliary bend angle (CBA) of airway cilia. Moreover, Ca2+‐dependent PDE1A existing in the CBF‐regulating metabolon of cilia modifies the CBF by regulating the cAMP accumulation. This study demonstrated that the CBF is regulated by a direct and an indirect action of [Ca2+]i; the direct action changes CBF mediated via [Ca2+]i, and the indirect action changes CBF mediated via cAMP, the accumulation of which is controlled by PDE1 activity. Upon reducing [Ca2+]i to various levels, the direct action decreases CBF and the indirect action increases CBF. The final CBF is determined by the extent of cAMP accumulation, which is determined by the amount of inhibition of PDE1 activity, dependent on a reduction in [Ca2+]i; a slight decrease induced by a nominally Ca2+‐free solution (no cAMP accumulation via PDE1) decreases CBF, and an extreme decrease induced by 50 μm BAPTA‐AM increases CBF via cAMP accumulation by inhibiting PDE1 in a similar manner to a PDE1 inhibitor (8MmIBMX). The increase in CBA in response to a reduction in [Ca2+]i is smaller than the increase in CBF, because no PDE1A exists in the CBA‐regulating metabolon. On the contrary, an increase in [Ca2+]i induced by ionomycin, which decreases cAMP accumulation by PDE1A activation, caused a slower procaterol‐stimulated increase in CBF than that decreased by a Ca2+‐free solution. A decrease in [Ca2+]i stimulates cAMP accumulation, whereas an increase in [Ca2+]i inhibits cAMP accumulation in airway ciliary cells. Thus, changes in [Ca2+]i modulate CBF and CBA via cAMP accumulation by controlling the activity of PDE1.