Efficient mucociliary transport relies on efficient regulation of ciliary beating
Introduction
Cilia are cellular protrusions covered by cellular membrane, which exist in a wide range of organisms and tissues from protozoa to the digestive, reproductive and respiratory system of vertebrates. Their main function is propulsion of water or mucus. Mucus-bearing ciliary systems are composed of three layers: an epithelial layer of ciliary cells; periciliary liquid of low viscosity, which surrounds the cilia; and the upper mucus layer, which is propelled by the cilia. The respiratory mucociliary epithelium is a synchronized and highly effective waste-disposal system. It uses mucus as a vehicle, driven by beating cilia, to transport unwanted particles, trapped in the mucus, away from the respiratory system. The ability of cilia, tiny hairlike protrusions (diameter 0.25 μm, length 5–7 μm and packing density 100–200 per cell), to propel steel beads of 1 mm in diameter at a speed of 0.5 mm/s is amazing (King et al., 1974). This titanic task is achieved due to the high degree of coordination between the individual cilia, and due to the ability of cilia to respond, quickly and for prolonged periods of time, to various stimuli by increasing drastically the ciliary beat frequency (CBF).
The ciliary machinery can function in at least two different modes: a low rate of beating that requires only ATP and most probably involves only the ciliary motor, and a high rate of beating that involves, in addition, a controlling device regulated by second messengers (Ma et al., 2002). To enable response to varying environmental conditions, ciliary cells possess a relatively large variety of different receptors capable of inducing intracellular events that lead to CBF enhancement, including purinergic, adrenergic and cholinergic receptors (Verdugo et al., 1980, Ovadyahu et al., 1988, Sanderson and Dirksen, 1989, Villalon et al., 1989, Mason et al., 1991, Weiss et al., 1992, Wong and Yeates, 1992, Gheber et al., 1995, Salathe et al., 1997, Zagoory et al., 2001, Salathe, 2007).
The periodic beating of cilia is achieved by the function of its complex internal apparatus (Satir and Christensen, 2007). Its core, the axoneme, consists of nine microtubule pairs (doublets) encircling the central pair. Adjacent doublets are linked by nexin filaments, whereas the central pair is connected to the surrounding microtubules by radial spokes. These links provide both structural stability and elasticity, allowing repetitive bending of the axoneme. The beating is powered by the activity of the microtubule-based dynein motor protein, which is attached to the outer microtubule doublets and utilizes ATP hydrolysis to produce active sliding of adjacent microtubule doublets (Summers and Gibbons, 1971). There are both inner and outer dynein arms on each doublet, and they occur in equal spacing along all of the doublet's lengths (Avolio et al., 1986).
This review will attempt to summarize the current state of knowledge regarding the mechanistic aspects of ciliary beating as well as the intricate intracellular signaling machinery regulating ciliary activity.
Section snippets
Physical properties of mucociliary transport
The beat pattern of mucus-propelling cilia is asymmetric. It consists of two main parts or strokes, the fast effective stroke and the slower recovery stroke (Fig. 1). During the effective stroke, the cilia are nearly in an upright position, moving in a plane perpendicular to the cell surface (Sanderson and Sleigh, 1981). This enables ciliary tips to embed in the mucus and propel it. During the recovery stroke, the cilia are bent, moving in an incline to the cell surface plane and avoiding
Regulation of ciliary beating by calcium
Many cellular events are triggered by changes in the cytoplasmic concentration of calcium ions (Berridge et al., 2000, Berridge et al., 2003, Petersen et al., 2005, Case et al., 2007). Calcium ions bind to many different cellular proteins, modifying their activity and consequently affecting the behavior of the entire cell. It is well established that Ca2+ is an important regulator of ciliary beating. In water-propelling cilia, calcium influx through voltage-gated calcium channels is responsible
Integration of signaling pathways regulating ciliary beating
In addition to Ca2+, cAMP and/or cGMP are important modulators of ciliary activity in a variety of ciliary systems (Tamaoki et al., 1989, Lansley et al., 1992, Geary et al., 1995, Yang et al., 1996, Braiman et al., 1998, Braiman et al., 2001b, Uzlaner and Priel, 1999, Zagoory et al., 2002, Zhang and Sanderson, 2003, Wyatt et al., 2005, Schmid et al., 2006, Salathe, 2007). The cAMP-dependent protein kinase (PKA) has been shown to phosphorylate specific axonemal targets that increase the forward
Summary
The respiratory mucociliary epithelium is a highly effective waste-disposal system. This task is achieved due to the high degree of coordination between the individual cilia, and due to the ability of cilia to increase drastically the ciliary beat frequency in response to various stimuli. On an active ciliary area there is a phase difference between beating cilia, creating a wave often referred to as the “metachronal wave” or “metachronism”, which allows for a large number of individual cilia
References (71)
- et al.
Feasibility of a sustained steep Ca2+ gradient in the cytosol of electrically non-excitable cells
J. Theor. Biol.
(2000) - et al.
Intracellular stores maintain stable cytosolic Ca2+ gradients in epithelial cells by active Ca2+ redistribution
Cell Calcium
(2001) - et al.
Evolution of calcium homeostasis: from birth of the first cell to an omnipresent signalling system
Cell Calcium
(2007) - et al.
Extraction of cilium beat parameters by the combined application of photoelectric measurements and computer simulation
Biophys. J.
(1997) - et al.
Effect of Ca2+ on the ciliary beat frequency of skinned dog tracheal epithelium
Respir. Physiol.
(1985) Families of phosphoinositide-specific phospholipase C: structure and function
Biochim. Biophys. Acta
(1998)- et al.
A realistic model of biphasic calcium transients in electrically nonexcitable cells
Biophys. J.
(1997) - et al.
Simultaneous measurement of ciliary beating and intracellular calcium
Biophys. J.
(1994) - et al.
Regulation of airway ciliary activity by Ca2+: simultaneous measurement of beat frequency and intracellular Ca2+
Biophys. J.
(1999) - et al.
Protein kinase C induced calcium influx and sustained enhancement of ciliary beating by extracellular ATP
Cell Calcium
(1997)
Calcium-mediated, purinergic stimulation and polarized localization of calcium-sensitive adenylyl cyclase isoforms in human airway epithelia
FEBS Lett.
Calcium signalling: past, present and future
Cell Calcium
Endoplasmic reticulum calcium tunnels integrate signalling in polarised cells
Cell Calcium
Update on mechanism and catalytic regulation in the NO synthases
J. Biol. Chem.
Forces applied by cilia measured on explants from mucociliary tissue
Biophys. J.
The forces applied by cilia depend linearly on their frequency due to constant geometry of the effective stroke
Biophys. J.
The long and arduous road to CRAC
Cell Calcium
Stimulus–response coupling in mammalian ciliated cells. Demonstration of two mechanisms of control for cytosolic [Ca2+]
Biophys. J.
Structures attached to doublet microtubules of cilia: computer modeling of thin-section and negative-stain stereo images
Proc. Natl. Acad. Sci. U.S.A.
Calcium signalling: dynamics, homeostasis and remodelling
Nat. Rev. Mol. Cell Biol.
The versatility and universality of calcium signalling
Nat. Rev. Mol. Cell Biol.
Enhancement of CBF is dominantly controlled by PKG and/or PKA
The role of cyclic nucleotide pathways and calmodulin in ciliary stimulation
PKA induces Ca2+ release and enhances ciliary beat frequency in a Ca2+-dependent and -independent manner
Am. J. Physiol.
Calcium regulation of ciliary beat frequency in human respiratory epithelium in vitro
J. Physiol.
Calcium in cell injury and death
Annu. Rev. Pathol.
Bioelectric control of ciliary activity
Science
Characterization of metachronal wave of beating cilia on frog's palate epithelium in tissue culture
J. Physiol.
Role of CNP in human airways: cGMP-mediated stimulation of ciliary beat frequency
Am. J. Physiol.
Intracellular Ca2+ regulates the phosphorylation and the dephosphorylation of ciliary proteins via the NO pathway
J. Gen. Physiol.
Effect of viscosity on metachrony in mucus propelling cilia
Cell Motil. Cytoskeleton
On metachronism in ciliary systems: a model describing the dependence of the metachronal wave properties on the intrinsic ciliary parameters
Cell Motil. Cytoskeleton
Metachronal activity of cultured mucociliary epithelium under normal and stimulated conditions
Cell Motil. Cytoskeleton
Extracellular ATP binding proteins as potential receptors in mucociliary epithelium: characterization using [32P]3′-O-(4-benzoyl)benzoyl ATP, a photoaffinity label
J. Membr. Biol.
Evidence for functional P2X4/P2X7 heteromeric receptors
Mol. Pharmacol.
Cited by (54)
Nonreciprocal oscillations of polyelectrolyte gel filaments subject to a steady and uniform electric field
2023, Journal of the Mechanics and Physics of SolidsSuper resolution microscopy analysis reveals increased Orai1 activity in asthma and cystic fibrosis lungs
2023, Journal of Cystic FibrosisThe effect of erdosteine on airway defence mechanisms and inflammatory cytokines in the settings of allergic inflammation
2019, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :According to the mentioned and based on the known activities of erdosteine, it is possible that it may reduce the mucus visco-elasticity and promote the MCC indirectly through antioxidant activity as well as directly through the disruption of disulphide bonds [25]. But, on the other hand, it must be highlighted that changes in the properties of mucus layer may not always guarantee an increase in MCC since its efficiency relies on the kinematic parameters of cilia, which provide the force for the forward mucus transport [26]. In principle, the faster the cilia beat, the higher rate of mucus transport will be.
Respiratory System, Mediastinum, and Pleurae
2017, Pathologic Basis of Veterinary Disease Expert ConsultSuccessful treatment of chronic lower respiratory tract infection by macrolide administration in a patient with intralobar pulmonary sequestration and primary ciliary dyskinesia
2015, Respiratory Medicine Case ReportsCitation Excerpt :While the mean ciliary beat frequency of healthy children was found to be 12.8/sec, the mean ciliary beat frequencies were 8.1, 2.3, and 0.8 in patients with an isolated inner dynein arm defect, isolated outer dynein arm defect, and combined defects of inner and outer arms, respectively [16]. Mucociliary clearance is a critical determinant of the host airway defense against infection in PCD patients [17], and the clearance is dependent on ciliary beat frequency [18]; thus, in PCD patients with an isolated inner dynein arm defect, the degree and incidence of bronchiectasis may be less severe and less frequent compared to PCD patients with another type of ciliary defect. Although a standard clinical approach to treatment of recurrent respiratory tract infection in PCD patients has not been defined, the use of antibiotic therapy against the most frequently isolated agents such as S. aureus, Streptococcus pneumoniae and Haemophilus influenzae has been a common and effective treatment [19].
Impact of Bepanthen<sup>®</sup> and dexpanthenol on human nasal ciliary beat frequency in vitro
2023, European Archives of Oto-Rhino-Laryngology