The Physiology of Cilia and Mucociliary Interactions

Satir, Peter; Sleigh, M. A.

doi:10.1146/annurev.ph.52.030190.001033

Cited by 218 publications

(102 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A primary determinant of mucus transport is the CBF, which can be regulated by different signals (2) with increases in intracellular Ca 2ϩ being particularly relevant (1). Although elevations of intracellular [Ca 2ϩ ] accelerate CBF, Ca 2ϩ signals are most efficient in regulating CBF when produced at the base of the cilia (30).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…In this analogy, cilia provide the power, whereas the mucus serves as the viscoelastic belt (1). A critical factor regulating the velocity of mucociliary transport is the ciliary beat frequency (CBF), a mechanism in which cytosolic Ca 2ϩ plays a major role (1,2). Increases in cytosolic Ca 2ϩ are associated with increases in CBF (3,4), although the ultimate molecular mechanism explaining CBF regulation by Ca 2ϩ remains controversial (3).…”

mentioning

confidence: 99%

See 2 more Smart Citations

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

Lorenzo

Liedtke

Sanderson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

176

171

View full text Add to dashboard Cite

The rate of mucociliary clearance in the airways is a function of ciliary beat frequency (CBF), and this, in turn, is increased by increases in intracellular calcium. The TRPV4 cation channel mediates Ca 2؉ influx in response to mechanical and osmotic stimuli in ciliated epithelia. With the use of a TRPV4-deficient mouse, we now show that TRPV4 is involved in the airways' response to physiologically relevant physical and chemical stimuli. Ciliary TRPV4 expression in tracheal epithelial cells was confirmed with immunofluorescence in TRPV4 ؉/؉ mice. Ciliated tracheal cells from TRPV4 ؊/؊ mice showed no increases in intracellular Ca 2؉ and CBF in response to the synthetic activator 4␣-phorbol 12,13-didecanoate (4␣PDD) and reduced responses to mild temperature, another TRPV4-activating stimulus. Autoregulation of CBF in response to high viscosity solutions is preserved in TRPV4 ؊/؊ despite a reduced Ca 2؉ signal. More interestingly, TRPV4 contributed to an ATPinduced increase in CBF, providing a pathway for receptor-operated Ca 2؉ entry but not store-operated Ca 2؉ entry as the former mechanism is lost in TRPV4 ؊/؊ cells. Collectively, these results suggest that TRPV4 is predominantly located in the cilia of tracheal epithelial cells and plays a key role in the transduction of physical and chemical stimuli into a Ca 2؉ signal that regulates CBF and mucociliary transport. Moreover, these studies implicate the participation of TRPV4 in receptor-operated Ca 2؉ entry.ATP ͉ trachea ͉ temperature ͉ transient receptor potential channel ͉ store-operated calcium entry I n mammalian airways, ciliated and mucus-secreting epithelial cells form a structural and functional unit that functions as a conveyor belt system for particle transport. In this analogy, cilia provide the power, whereas the mucus serves as the viscoelastic belt (1). A critical factor regulating the velocity of mucociliary transport is the ciliary beat frequency (CBF), a mechanism in which cytosolic Ca 2ϩ plays a major role (1, 2). Increases in cytosolic Ca 2ϩ are associated with increases in CBF (3, 4), although the ultimate molecular mechanism explaining CBF regulation by Ca 2ϩ remains controversial (3). Both mechanical and chemical (paracrine) stimulation of epithelial ciliated cells can lead to an increase in intracellular Ca 2ϩ concentration and the consequent enhancement of CBF (2). ATP-mediated activation of G protein-coupled receptors, typically P2Y receptors, is one of the strongest signals known to increase CBF (2). As with many other agonists of G proteincoupled receptors, ATP promotes both the release of Ca 2ϩ from inositol trisphosphate (IP 3 )-sensitive intracellular stores and Ca 2ϩ entry across the plasma membrane (4), and the latter process is more evident at micromolar concentrations of ATP where a sustained Ca 2ϩ influx occurs. The stimulation of Ca 2ϩ influx involves signaling from the depleted stores to plasma membrane Ca 2ϩ channels (store-operated calcium entry, SOCE; also known as capacitative Ca 2ϩ entry) and/or through a phospholipase...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

Lorenzo

Liedtke

Sanderson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

176

171

View full text Add to dashboard Cite

show abstract

“…1 They play important roles in fluid movement, cell migration, and sensory reception. 2,3 Multiciliated cells lining the trachea have a crucial function in mucociliary clearance, while ependymal cells lining the ventricles in the brain are involved in the transport of cerebrospinal fluid. 4 Although much less is understood with regards to primary cilia in mammals, they have been implicated as mechanosensors in the kidney that detect fluid flow through the lumen of the collecting ducts.…”

mentioning

confidence: 99%

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Zhang

Davenport

Croyle

et al. 2005

Laboratory Investigation

100

View full text Add to dashboard Cite

While relatively ignored for years as vestigial, cilia have recently become the focus of intense interest as organelles that result in severe pathologies when disrupted. Here, we further establish a connection between cilia dysfunction and disease by showing that loss of polaris (Tg737), an intraflagellar transport (IFT) protein required for ciliogenesis, causes abnormalities in the exocrine and endocrine pancreas of the Tg737 orpk mouse. Pathology is evident late in gestation as dilatations of the pancreatic ducts that continue to expand postnatally. Shortly after birth, the acini become disorganized, undergo apoptosis, and are largely ablated in late stage pathology. In addition, serum amylase levels are elevated and carboxypeptidase is abnormally activated within the pancreas. Ultrastructural analysis reveals that the acini undergo extensive vacuolization and have numerous 'halo-granules' similar to that seen in induced models of pancreatitis resulting from duct obstruction. Intriguingly, although the acini are severely affected in Tg737 orpk mutants, cilia and Tg737 expression are restricted to the ducts and islets and are not detected on acinar cells. Analysis of the endocrine pancreas in Tg737 orpk mutants revealed normal differentiation and distribution of cell types in the islets. However, after fasting, mutant blood glucose levels are significantly lower than controls and when challenged in glucose tolerance tests, Tg737 orpk mutants exhibited defects in glucose uptake. These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis.

show abstract

“…Despite the structural similarity, each of these axonemes is specialized for a particular function. Thus, the waveform of a sperm flagellum (3), which functions to propel the sperm forward, is very different from the coordinated beating of respiratory tract cilia, which function to transport mucus over airway surfaces (4). Moreover, the regulation of the activity of each specialized axoneme is also likely to be unique.…”

mentioning

confidence: 99%

Identification of Dynein Heavy Chain 7 as an Inner Arm Component of Human Cilia That Is Synthesized but Not Assembled in a Case of Primary Ciliary Dyskinesia

Zhang

O’Neal

Randell

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Although the basic structure of the axoneme has been highly conserved throughout evolution, the varied functions of specialized axonemes require differences in structure and regulation. Cilia lining the respiratory tract propel mucus along airway surfaces, providing a critical function to the defense mechanisms of the pulmonary system, yet little is known of their molecular structure. We have identified and cloned a dynein heavy chain that is a component of the inner dynein arm. Bronchial epithelial cells were obtained from normal donors and from a patient with primary ciliary dyskinesia (PCD) whose cilia demonstrated an absence of inner dynein arms by electron microscopy. Cilia from normal and PCD cells were compared by gel electrophoresis, and mass spectrometry was used to identify DNAH7 as a protein absent in PCD cilia. The full-length DNAH7 cDNA was cloned and shares 68% similarity with an inner arm dynein heavy chain from Drosophila. DNAH7 was induced during ciliated cell differentiation, and immunohistochemistry demonstrated the presence of DNAH7 in normal cilia. In cilia from PCD cells, DNAH7 was undetectable, whereas intracellular DNAH7 was clearly present. These studies identify DNAH7 as an inner arm component of human cilia that is synthesized but not assembled in a case of PCD.The basic structure of the axoneme consisting of nine outer microtubule doublets surrounding a central pair (9 ϩ 2 arrangement) is one of the most highly conserved structures in all of cell biology (1, 2). The 9 ϩ 2 arrangement is found in many diverse organisms ranging from the flagella of Chlamydomonas and the gill cilia of freshwater mussels to the sperm flagella of sea urchins and respiratory tract cilia of humans. Despite the structural similarity, each of these axonemes is specialized for a particular function. Thus, the waveform of a sperm flagellum (3), which functions to propel the sperm forward, is very different from the coordinated beating of respiratory tract cilia, which function to transport mucus over airway surfaces (4). Moreover, the regulation of the activity of each specialized axoneme is also likely to be unique. For example, increases in Ca 2ϩ have been shown to stimulate ciliary beating of tracheal epithelial cells (5), whereas Paramecium cilia respond to increased Ca 2ϩ by reversing the direction of beating (6). These functional differences are a reflection of unique modifications of the structure and composition of each specialized axoneme. For example, Chlamydomonas flagella have three outer arm dynein heavy chains (DHCs) 1 (7), whereas outer arms from mammalian respiratory cilia have been reported to contain only two DHCs (8). Therefore, it is clear that although the basic structure and components of cilia and flagella are conserved, specialization of function has resulted in important variations of structure and regulation among the different motile axonemes.The Chlamydomonas flagellum represents the most thoroughly characterized axonemal structure. Through the use of readily obtained mutants and comp...

show abstract

The Physiology of Cilia and Mucociliary Interactions

Cited by 218 publications

References 27 publications

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Identification of Dynein Heavy Chain 7 as an Inner Arm Component of Human Cilia That Is Synthesized but Not Assembled in a Case of Primary Ciliary Dyskinesia

Contact Info

Product

Resources

About