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

Abstract

Intracellular Ca²⁺ concentration ([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 exists in the CBF regulating metabolon of cilia. This study demonstrated that 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, accumulation of which is controlled by the 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 extents of cAMP accumulation, which are determined by PDE1 activities inhibited dependent on [Ca²⁺]_i decreases; 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 via inhibiting PDE1 similarly to a PDE1 inhibitor (8MmIBMX). CBA increase in response to [Ca²⁺]_i decreases is smaller than CBF increase, because of no existence of PDE1A in the CBA regulating metabolon. Contrary, an [Ca²⁺]_i increased by ionomycin, which decreases cAMP accumulation by PDE1A activation, caused a slower procaterol-stimulated CBF increase than that decreased by a Ca²⁺-free solution. A decrease in [Ca²⁺]_i stimulates cAMP accumulation, while 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 PDE1 activity.

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