Nitric Oxide Production and Signaling in Motile Cilia

Nitric oxide (NO) is an important regulator of motile cilia. Coordinated ciliary beating moves mucus, extracellular fluids, or cells across tissue surfaces and, during embryonic development, drives the establishment of correct organ left–right asymmetry. The connection between NO and cilia function is particularly evident in primary ciliary dyskinesia (PCD), where reduced nasal NO is a diagnostic hallmark, although whether it contributes to or results from ciliary dysfunction remains unclear. Studies of PCD and other airway diseases also show that NO levels do not necessarily correlate with nitric oxide synthase (NOS) expression or activity, indicating that NO bioavailability in ciliated tissues is regulated by additional mechanisms. Despite decades of evidence linking NO to ciliary function, fundamental questions remain regarding how NO is produced and regulated within ciliated cells, how NO signaling is spatially organized within the ciliary microenvironment, and how it reaches the axoneme to regulate ciliary structure and motility. In this review, we examine these questions focusing on soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling, S-nitrosylation, and emerging redox-dependent mechanisms regulating NO bioavailability in motile cilia.