Biol. Cell (2011) 103, 159169 (Printed in Great Britain) doi:10.

1042/BC20100120
Review

Ciliary beat co-ordination by calcium

Andreas Schmid and Matthias Salathe1
Division of Pulmonary and Critical Care and Sleep Medicine, Miller School of Medicine, University of Miami, RMSB R-47, 1600 NW 10th
Avenue, Miami, FL 33136, U.S.A.

Motile cilia in the airway epithelium are the engine for mucociliary clearance, the mechanism responsible for
cleaning the airways from inhaled particles. Human airway epithelial cilia appear to have a slow constitutive rate of
beating, driven by inherent and spontaneous dynein ATPase activity. Additionally, cilia can increase their beating
frequency by activation of several different control mechanisms. One of these controllers is calcium. Its intracellular
concentration is regulated by purinergic and acetylcholine receptors. Besides the rate regulatory effect of calcium
on ciliary beat, calcium is also involved in synchronizing the beat among cilia of one single cell as well as between
cilia on different cells. This article gives an overview of the complex effects of calcium on the beating of motile cilia
in the airways.

Introduction approx. 5 s, a considerable challenge even for Usain

Cilia are tiny hair-like protrusions of the cell. In gen-
eral, cilia are sensory organelles. Each cilium is en-
veloped by a ciliary membrane, which is contiguous
with the plasma membrane at the base of each cilium
and contains a variety of cilia-specific proteins and
signalling receptors (Pazour et al., 2005). The ability
of the ciliary membrane to maintain its specific com-
position has recently been associated with the pres-
ence of septins at the ciliary base (Hu et al., 2010).
Many cilia are equipped with dynein motors and ad-
ditional axonemal complexes, making them motile
devices. Hundreds of motile cilia cover the luminal
surface of epithelial cells in the airways, Fallopian
tubes and cerebral ventricles, revealing the typical
9+2 microtubular cross-section structure in electron
microscopic pictures.
Beating cilia produce significant amounts of power,
illustrated by the 100-m-long, ciliated Paramecium
that can swim with a velocity in the order of 1 mm/s
(Niedermayer et al., 2008). Extrapolated to human
size, a person would be able to run the 100 m dash in
1 Towhom correspondence should be addressed (email
msalathe@med.miami.edu).
Key words: calcium, ciliary beat frequency (CBF), purinergic signalling,
acetylcholine (ACh), pannexin, synchronization.
Abbreviations used: AC, adenylate cyclase; ACh, acetylcholine; CaM,
calmodulin; CBF, ciliary beat frequency; CFTR, cystic fibrosis transmembrane
conductance regulator; cGMP, cyclic guanosine monophosphate; Cx,
connexon; IP3 , inositol triphosphate; PKA, protein kinase A; PKG, protein
kinase G; PLC, phospholipase C; TRPV4, transient receptor potential cation
channel subfamily V member 4; VSP, voltage sensor-dependent phosphatase;
UTP, uridine triphosphate.
Bolt, currently the fastest man on earth, who per-
formed this task in the world record time of 9.58 s.
In this review, we will focus mainly on the effect of
calcium on motile cilia of mammalian airway epi-
thelial cells, where cilia are relatively long (7 m)
and have a diameter of 0.250.3 m (Levin et al.,
1997).
The primary task of motile cilia in the airways
is to propel mucus, loaded with inhaled particles,
out of the lung. The ciliary machinery can func-
tion in at least two different modes: a slow, con-
stitutive rate of beating that seems governed by the
inherent and spontaneous dynein ATPase activity
and a high rate of beating that involves controlling
mechanisms to increase the dynein ATPase activity
through second messengers (Ma et al., 2002; Salathe
and Bookman, 1999). In the airways, CBF (ciliary
beat frequency) is stimulated via three ubiquitous
second messengers: Ca2+ , cGMP (cyclic guanosine
Motile cilia: Motile cilia consist of a microtubular axoneme surrounded by a
membrane that is in continuation with the plasma membrane of the cell. The
ultrastructure of axonemes has been well preserved throughout evolution. It
is made up of microtubules, dynein arms, radial spokes and interdoublet
links. In human airways, cilia are restricted to the conductive airways
proximal to the respiratory bronchioles. While the size of the total alveolar
surface of a normal human lung is approx. 85 m2 , the ciliated surface
measures only approx. 0.15 m2 . Cilia are beating in the airways at a certain
frequency.
CBF (ciliary beat frequency): CBF has a slow constitutive rate that can be
accelerated by several mediators such as cAMP, cGMP and calcium. CBF
can be measured in airliquid interface cultures in real time, using
differential interference contrast video microscopy.

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 A. Schmid and M. Salathe

Figure 1 Illustration of different effects of calcium on the regulation of CBF

Please see text for a detailed description of the different pathways. Briefly, Ca2+ is released from intracellular storages by IP3 ,
activated by P2 Y2 through ATP and muscarinergic receptors by ACh. Mechanostimulation and high viscosity increases intracel-
lular Ca2+ by ATP release through pannexin with stimulation of P2 Y2 and through activation of TRPV4. Released Ca2+ binds to
CaM and leads to increased production of cAMP and cGMP, which is increasing CBF over PKA and PKG by phosphorylation of
dynein arms. Abbreviations: AC, adenylate cyclase; ACh, acetylcholine; Ca2+ CaM, calciumcalmodulin complex; IP3 , inositol
triphosphate; IP3 R, inositol triphosphate receptor; M, muscarinergic receptor; NOS, nitric oxide synthethase; PANX, pannexin;
PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLC, phospholipase C; sAC, soluble adenylate cyclase;
TRPV4, transient receptor potential cation channel subfamily V member 4.

monophosphate) and cAMP (Salathe, 2007) (Fig-
ure 1). Each of these messengers seem, at least to a
certain degree, to increase CBF via distinct pathways
(Zagoory et al., 2002). On the other hand, these dis-
tinct pathways can converge on common molecules
to regulate CBF. For instance, Ca2+ has been shown
to directly influence CBF, but can simultaneously
activate Ca2+ -dependent AC (adenylate cyclase) iso-
forms that are expressed in mucociliary epithelia,
thereby increasing cAMP production (Nlend et al.,
2007). CalciumCaM (calmodulin) complexes activ-
ate NOSs (nitric oxide synthases; Stuehr et al., 2004),
leading to stimulation of the cGMPPKG (protein
kinase G) pathway. The application of CaM inhib-
itors suppresses agonist-induced elevations of both
cAMP and cGMP (Zagoory et al., 2002). PKA (pro-
tein kinase A) activity has been shown to augment IP3
(inositol triphosphate)-dependent Ca2+ mobilization
in mucociliary cells from frogs (Braiman et al., 1998),
while PKG activity is necessary for maintaining Ca2+
influx in rabbit airway ciliary epithelium. The cross-
talk between the three pathways is evident not only at
the level of second messenger production but also
at the level of their effect on ciliary beating. In-
hibition of the nitric oxidecGMPPKG signalling
pathway at any of its steps abolishes the CBF

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Role of calcium in CBF
enhancement in the presence of high intracellular cal-
cium concentration, at least in rabbit cells (Uzlaner
and Priel, 1999), and vice versa, CBF activation in
patch-clamped rabbit epithelial cells requires the
presence of cyclic nucleotides for calcium to be ef-
fective, while the presence of calcium enhances CBF
stimulation produced by cyclic nucleotides in the
same system (Ma et al., 2002).
Action of calcium on cilia
Calcium ions are ubiquitous second messengers that
take part in the regulation of virtually all cellular
processes. The influence of calcium on ciliary beating
has been known for a long time. Ca2+ can exert its
function by binding and/or regulating the activity
of a wide range of cellular proteins, such as CaM,
protein kinases and phosphatases, AC, phosphodi-
esterases, cytoskeletal elements, membrane channels
and ATPases (Rasmussen and Rasmussen, 1990). As
in most electrically non-excitable cells, signalling via
increased [Ca2+ ]i in mucociliary epithelium mostly
depends on the activation of PLC (phospholipase C).
Triggering of the P2 -purinergic or muscarinic recept-
ors by ATP or ACh (acetylcholine) respectively results
in the activation of PLC- (Katan, 1998). The ac-
tivated enzyme hydrolyses phosphatidylinositol-4,5
bisphosphate to IP3 (Irvine, 2003), which stimulates
the release of Ca2+ from intracellular stores. Activ-
ated PLC- also activates PKC (protein kinase C)
signalling pathway (Nishizuka, 1988) over diacygly-
cerol, allowing extracellular calcium flux into the cell
(Levin et al., 1997) and release of calcium from intra-
cellular stores into the cytosol (Figure 1). Since airway
epithelial cells are polarized structures with cilia on
their apical membranes, calcium concentrations are
especially high in the sub-membranous areas to af-
fect ciliary beat (Braiman and Priel, 2008). Based
on the importance of calcium for many different
pathways, it seems unlikely that changes in [Ca2+ ]i
would affect the whole cytosol of the cell, assuming
that there are mechanisms in place to maintain dif-
ferent concentrations of calcium within the cytosol
Mucociliary clearance: Mucociliary clearance is the mechanism responsible for removing inhaled dust and micro-organisms from the airways. Its three
components are cilia, periciliary fluid and mucus. Cilia are hair-like structures, beating in a low-viscosity periciliary fluid. The composition and height of this fluid
is tightly regulated by different membrane channels, such as CFTR, ENaC (epithelial sodium channel) and calcium-dependent chloride channels. Mucus is
produced and excreted into the airways by submucosal glands and goblet cells. A disturbance of any of these components leads to airway diseases such as
primary ciliary dyskinesia (cilia), cystic fibrosis (periciliary fluid) or chronic bronchitis (mucus overproduction).
Review
(Braiman and Priel, 2008). It appears that storage
and release of Ca2+ in different cell compartments
are responsible for this apical versus basolateral con-
centration difference in the cytosol (Braiman et al.,
2000; Braiman and Priel, 2001). It is clear that these
mechanisms maintaining a difference in calcium con-
centration within the cell are dependent on energy,
since calcium concentrations within the liquid phases
of the cell would equilibrate as per the second law of
thermodynamics (Braiman and Priel, 2008; Petersen
and Verkhratsky, 2007).
Besides the release from intracellular stores, cal-
cium reaches the axoneme also through channels
in the ciliary membrane. Several different voltage-
dependent Ca2+ channels have been identified in cili-
ates (Andrivon, 1988) and Ca2+ -conducting P2 X re-
ceptor channels were found in the proximal portion
of the cilia of rabbit airway epithelial cells (Ma et al.,
2006).
The direct effect of Ca2+ on the axoneme is still
not well understood. In Chlamydomonas reinhardtii,
Ca2+ manifests its effect on ciliary beat over binding
to calcium-sensitive proteins, such as CaM, which
associates with radial spokes and the central appar-
atus of the flagella (Dymek and Smith, 2007). It
was also demonstrated that calcium-related dynein
movements in Chlamydomonas are mediated by CaM
(Smith, 2002). Additionally, Ca2+ seems to have
a direct effect on the movement of certain dynein
arms in Chlamydomonas (Sakato et al., 2007). The
effect of CaM on cilia of mammals is less clear. Ini-
tial reports showed an effect of CaM inhibitors on
CBF (Di Benedetto et al., 1991), but these inhibit-
ors were later found to be ciliotoxic. Less toxic in-
hibitors did not have an effect on CBF (Salathe and
Bookman, 1999). Additionally, no CaM targets were
found in the axoneme of mammalian cilia (Salathe,
2007).
The question about the physiological relevance of
changes in CBF with respect to mucociliary clear-
ance is frequently raised. ACh and ATP as well as
cAMP stimulation leads to CBF increases 1530 %
above baseline in tracheal cell cultures in our hands.
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Seybold et al. (1990) examined the relation between
CBF changes and mucociliary clearance and found
that a 16 % increase in CBF correlated with a 56 %
increase in mucociliary transport velocity in isolated
whole tracheas.
Purinergic receptors
ATP can release Ca2+ from intracellular stores and
increase Ca2+ influx from the extracellular space via
G-protein-coupled P2 Y2 receptors as mentioned
above. The massive (45-fold) initial Ca2+ release
from the intracellular storage occurs by PLC/IP3 ac-
tivation (Figure 1) and leads to a rapid initial increase
in CBF, where the increase in beat frequency follows
the rise in [Ca2+ ]i within a single beat cycle in all
tested mammals (Evans and Sanderson, 1999; Levin
et al., 1997; Salathe and Bookman, 1999). The sub-
sequent changes in CBF and Ca2+ in response to ATP,
however, have been found to vary between different
species and even between different locations (proxi-
mal versus distal airways) within the same species.
In rabbits, a plateau of increased CBF that follows
the CBF peak is related to calcium influx from the
extracellular space, since it was not maintained in a
calcium-free perfusate (Korngreen and Priel, 1996;
Levin et al., 1997). This influx may be associated
with stimulation of P2 X receptors in the airways of
rabbits (Korngreen et al., 1998). Similar mechanisms
seem to be in place in the proximal airways of rats
(Hayashi et al., 2005). Interestingly, the distal air-
ways of mice and rats did not react similarly to ATP
stimulation. In rats, ATP or UTP (uridine triphos-
phate) stimulation in distal airways did not lead to an
increase in CBF, whereas emptying of the intracellular
stores with thapsigargin and ionomycin did, suggest-
ing the absence of purinergic receptors in peripheral
airways of these species (Hayashi et al., 2005). Even
more interesting, no increase in CBF upon ATP stim-
ulation was found in the peripheral airways of mice
even though ATP led to an increase in [Ca2+ ]i , indic-
ating that cilia were already maximally stimulated
(Delmotte and Sanderson, 2006). The missing effect
of forskolin on these cells supports this hypothesis.
In sheep, apical ATP exposure did not lead to any
plateau after the initial peak (Lieb et al., 2002).
In proximal human airways, a long-term (15 min),
high-dose ATP and UTP (100 M) stimulation leads
to a plateau response of CBF and [Ca2+ ]i (Lieb et al.,
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A. Schmid and M. Salathe
2002). Interestingly, upon short-term (1 min) ap-
ical exposure of airway epithelial cells to ATP at
low concentrations (10 M), there is no [Ca2+ ]i
plateau even though CBF remains elevated (Lieb
et al., 2002). The possibility that the plateau may
be related to products of ATP hydrolysis (adenosine)
was confirmed in the study by Morse et al. (2001),
but even in the absence of adenosine {for instance,
by using non-hydrolysable ATP[S] (adenosine-5 -[ -
thio]triphosphate) or UTP}, CBF remained elevated
well beyond the increase in [Ca2+ ]i (Lieb et al., 2002;
Zhang and Sanderson, 2003). This CBF plateau could
be blocked by PKA inhibition. In vivo intracellu-
lar cAMP measurement with a PKAFRET (fluor-
escence resonance energy transfer) system (Schmid
et al., 2006) revealed that cAMP was elevated on
ATP stimulation (Nlend et al., 2007), implicating
calcium-sensitive ACs (Figure 1). In fact, it has been
shown that calcium-sensitive AC1 and possibly AC8
are localized to the apical membrane of human airway
epithelial cells (Nlend et al., 2007), which could ex-
plain the calcium-related increase in cAMP, especially
since this increase was blocked by an AC inhibitor
(Nlend et al., 2007).
While extracellular ATP has now been recognized
as one of the most important paracrine mediators to
regulate mucociliary function, the exact mechanism
of ATP release from airway epithelial cells has been
a matter of debate. There is no doubt that ATP can
be released via vesicles, including mucin granules,
but additional, channel-mediated release has been
suggested, including release via Cxs (connexons; es-
pecially Cx43) and CFTR (cystic fibrosis transmem-
brane conductance regulator). Cx43 has been pro-
posed as a major ATP release channel (Cotrina et al.,
1998, 2000; Stout et al., 2002) because inhibitors
of gap junction interfered with ATP release (Evans
et al., 2006). There are many reasons why Cxs and
in particular Cx43 are unlikely channels for ATP
release, at least by themselves. For instance, Cx43
hemichannel activity requires extreme polarization
of the cell, which does not occur under physiolo-
gical conditions, at least not in airway epithelial
cells. These conditions, however, can be produced
by voltage clamping, from where these reports stem
(Contreras et al., 2003). Additionally, ATP release
has been demonstrated in Cx-free environments such
as erythrocytes and taste cells (Huang et al., 2007;
Locovei et al., 2006). Although there may be
Role of calcium in CBF
different mechanisms of ATP release to the lumen of
human airways, pannexin 1 has recently been shown
to play an important role in this process (Ransford
et al., 2009) and at least some of the experiments im-
plicating Cxs may have blocked pannexins. Pannexin
1 was found in the apical membrane of human airway
epithelial cells (cultures and tracheal sections) and
ATP release triggered by hypotonic stress could be
blocked by using pannexon inhibitors and shRNA
(short hairpin RNA) against pannexin 1 (Ransford
et al., 2009).
ACh
Beside purinergic signalling, ACh can induce similar
[Ca2+ ]i and CBF changes, at least in some mam-
malian species (Figure 1). Early data stemmed from
the frog oesophagus, where stimulation with 10 M
ACh lead to a fast [Ca2+ ]i increase with a plat-
eau of a few minutes, before [Ca2+ ]i reached pre-
stimulation levels. Simultaneously, CBF was increas-
ing fast and maintained an elevated plateau even
after [Ca2+ ]i had normalized (Zagoory et al., 2002).
These changes went hand in hand with an initial
peak of cGMP and an increase in cAMP during the
CBF plateau phase (Zagoory et al., 2002), indicat-
ing an influence of cGMP on the initial, fast CBF
increase and an influence of cAMP on the later plat-
eau phase. Inhibitors of PKG and PKA or cGMP
and cAMP production could block these plateau ef-
fects. It seemed that PKA contributed to the dura-
tion and the magnitude of the first phase, but was
obligatory for the existence of the second phase of
the ACh response (Zagoory et al., 2002). Interest-
ingly, it was shown that extracellular calcium had no
effects on these responses (Zagoory et al., 2001). In-
hibition of CaM moderately attenuated the response
of Ca2+ , but abolished completely both the first and
the second phase of the CBF enhancement. Thus,
it seems that calcium ions are essential for the el-
evation of cAMP or cGMP levels by ACh. Most
probably, calcium ions act by binding to CaM, form-
ing CaCaM complexes, which subsequently activ-
Purinergic signalling: Purinergic signalling in the human body is complex. There are over 20 different purinergic receptors. P1 receptors are stimulated by
adenosine and regulate intracellular cAMP concentrations. P2 X receptors are ligand-gated ion channels responsive to ATP. P2 Y receptors are G protein-coupled
receptors that are stimulated by ATP, ADP, UTP and UDP. P2 Y2 is the most important purinergic receptor for the regulation of ciliary beat. ATP stimulates P2 Y2
receptors to increase the intracellular calcium leading to an increase in CBF. It also increases chloride secretion in the periciliary space by activating
calcium-dependent chloride channels.
Review
ate AC and guanylyl cyclases (Zagoory et al., 2002)
(Figure 1).
Evaluations of ACh-induced changes in CBF and
[Ca2+ ]i in ciliated ovine tracheal epithelial cells re-
vealed changes similar to the ones described in the
frog esophagus. There was a sharp increase in CBF and
[Ca2+ ]i on stimulation with ACh, but in contrast to
the frog, there was a clear dependence on the avail-
ability of extracellular calcium (Salathe and Book-
man, 1995), at least for part of the response. It was
concluded that muscarinic receptors (M3) initiated
specific signalling pathways that act simultaneously
to increase and decrease [Ca2+ ]i and CBF (Salathe
et al., 1997). One possible source of ACh in vivo is
the extensive network of autonomic nerve fibres that
innervate the airway. This possibility is supported by
the demonstration of acetylcholinesterase-containing
nerves in association with the surface epithelium and
submucosal glands of the airway (Laitinen, 1985).
These nerve fibres may provide neural control of the
activity of cilia through the release of neurotransmit-
ters. Additionally, it has been reported that airway
epithelial cells themselves are able to synthesize ACh
(Wessler and Kirkpatrick, 2001).
Most interestingly, ACh not only leads to an in-
crease in CBF and [Ca2+ ]i , but also to a decrease
in CBF after blocking the release or the reuptake
of calcium from or to intracellular calcium storage
compartments (Salathe and Bookman, 1995; Salathe
et al., 1997, 2001). The underlying mechanism of
these decreases was related to Ca2+ uptake into mi-
tochondria (Salathe et al., 2001). In the physiological
context, this suggests that the action of ACh on CBF
should not be viewed as purely stimulatory. Rather,
cholinergic agonists can exert more subtle forms of
control and the effect of ACh on CBF will depend,
in part, on the state of repletion of the internal Ca2+
stores (Salathe and Bookman, 1995). However, the
response of human airway epithelial cells to ACh is
blunted compared to other species and in particular
ATP. Thus, the relevance of the findings in sheep and
other mammalian species to human airway epithelial
cells remains unknown.
www.biolcell.org | Volume 103 (4) | Pages 159169 163

Mechano-stimulation
The influence of mechanical forces on the regulation
of CBF has been a matter of debate. Two different
mechanical influences stand in the foreground of this
discussion: shear stress, by changing the radius of the
airway during regular breathing/coughing as well as
air flow above the cells, and increased viscosity of
airway secretions.
It has been shown that the application of shear
stress on the airway epithelium leads to an increase
in apical ATP release (Homolya et al., 2000; Tarran
et al., 2005) and to an increase in Ca2+ influx
into the cells (Sanderson and Dirksen, 1986). Re-
cently, it could also be shown that CBF increased
within minutes on shear stress application as small
as 10 3 Pa. CBF again decreased within minutes of
shear reduction in mouse airway epithelia (Winters
et al., 2007). The CBF response was not observed
in P2 Y2 / mice or on the application of the che-
lator EGTA and the calcium channel inhibitor La3+
(lanthanum) (Winters et al., 2007), suggesting the
involvement of ATP release and signalling via P2 Y2
receptors (Figure 1).
The hypothesis that mechanical stimulation might
be physiologically initiated by changes in mucus vis-
cosity has been debated for quite a while (Spungin and
Silberberg, 1984), but the cellular mechanism link-
ing the viscous load exerted by the presence of mucus
to the control of CBF remained unclear. The ver-
tebrate TRPV4 (transient receptor potential cation
channel subfamily V member 4) has been proposed
as an osmo- and mechano-sensitive channel (Arniges
et al., 2004; Liedtke et al., 2000, 2003). Studies in
hamster oviduct confirmed the expression of TRPV4
in ciliated cells (Andrade et al., 2005). Double stain-
ing with anti-acetylated alpha tubulin antibody to
mark the axoneme confirmed the ciliary localization
of TRPV4 (Lorenzo et al., 2008). Recently, a cross-
talk between the ATP-PLC-IP3 receptor pathway and
TRPV4 to initiate and maintain the oscillatory Ca2+
signal triggered by mechanical and osmotic stim-
uli has been reported (Fernandes et al., 2008) (Fig-
ure 1). The Ca2+ signal obtained after the addition of
20 M ATP showed clear differences between ciliated
TRPV4+/+ and TRPV4 / cells. Although cells of
both genotypes showed no statistical difference in
peak increases in Ca2+ , the sustained component was
reduced by 30 % in the latter (Lorenzo et al., 2008).
This effect appeared to be related to the participa-
164 
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C 2011 Portland Press Limited
A. Schmid and M. Salathe
tion of TRPV4 in receptor-operated calcium entry
but not in storage-operated calcium entry mechan-
isms, because ciliated tracheal cells from TRPV4 /
mice showed no deficiency in the Ca2+ influx eli-
cited by store depletion using thapsigargin (Lorenzo
et al., 2008). Another study showed that inhibition
of the membranous calcium transport channels with
Gd3+ (gadolinium) as well as clamping extracellular
Ca2+ to zero decreased the CBF response on increase
in a viscous extracellular load, whereas it did not
have any influence on baseline CBF (Andrade et al.,
2005). It could be shown that an extracellular load
with 5 % dextran solution did not change [Ca2+ ]i ,
whereas 30 % dextran did change [Ca2+ ]i signific-
antly (Andrade et al., 2005). These results suggested
that basal CBF is not under the influence of Ca2+
influx from the apical lumen.
Synchronization of the beat
(metachronicity)
Eukaryotic axonemal structures beat with two dis-
tinct waveforms. One is known as the ciliary wave-
form and the other as the flagellar waveform. The cili-
ary waveform involves an asymmetric beat/stroke-like
motion, with a power stroke and a recovery stroke.
In contrast, the flagellar waveform is symmetrical.
For example, mammalian respiratory epithelia use
the ciliary waveform to drive fluid flow in one dir-
ection, whereas sperms use the flagellar waveform to
push the cell forward. Some protists, however, have
the possibility to switch from ciliary to flagellar beat-
ing. Chlamydomonas uses its two flagella in a ciliary
waveform to pull the cell forward, but bright light or
mechanical stimulation induce a switch to flagellar
waveform that pushes the cell backwards, a beha-
viour known as the photoshock response (Quarmby,
2009). Recently, it has been described that calcium
may regulate the switch of this beating pattern. A
mutant of Chlamydomonas (ppr2) was found to have
a mutation in the CAV2 gene, which encodes a sub-
unit of a voltage-dependent calcium channel at the
distal end of each flagellum (Fujiu et al., 2009). Inter-
estingly, these mutants have a defective photophobic
(Matsuda et al., 1998) and mechano-shock response,
indicating that calcium influx through these distal
flagellar channels is needed to change from the ciliary
to the flagellar beating pattern in Chlamydomonas.
This finding and the fact that different concentrations
of calcium in Paramecium can change the direction of
Role of calcium in CBF
its movement (Naito and Kaneko, 1972) indicate the
importance of calcium for the regulation of the ciliary
beat form.
Voltage-dependent effects on motility have also
been described in multicellular organisms. In sea
urchin sperms, voltage-dependent calcium channels
are involved in the acrosome reaction and are im-
portant for sperm motility (Granados-Gonzalez et al.,
2005). Ciona intestinalis sperm tail membranes con-
tain VSPs (voltage sensor-dependent phosphatases)
(Murata et al., 2005), which may be involved in the
regulation of flagellar beat. A mammalian VSP homo-
logue gene is expressed in testis (Tapparel et al.,
2003). On the other hand, calcium also affects the
voltage-dependent conductance of other electrolytes,
such as the calcium-dependent chloride channel in
respiratory ciliated cells (Tarran et al., 2000).
Ciliary beating in metazoans commonly uses only
one waveform, which is the ciliary beating pattern
in the airway epithelium. Since the cells have up to
several hundreds of cilia, co-ordination of the beat of
all of these is crucial to be able to effectively transport
mucus. The mechanism of ciliary synchronization is
an interesting and still incompletely resolved prob-
lem. Several mechanisms have been suggested for
different species and organs, ranging from nervous
control for the frogs oropharyngeal cavity, neuro-
transmitters or local mediators that diffuse below the
basement membrane to ciliated cells, and membrane
potential in the oviduct. So far, a general and common
control mechanism for synchronized ciliary activity
has not been found and most of the mechanisms listed
above were never proven (Gheber and Priel, 1989).
Moreover, there is a general belief that control de-
creases towards higher forms of life (Aiello and Sleigh,
1972; Kinosita and Murakami, 1967).
It appears that synchronization among beating cilia
decreases as separation distance increases (Gheber and
Priel, 1989). Interestingly, flagella of individual sper-
matozoa and Spirochaeta balbianii start to beat syn-
chronously, if their heads are close (Gray, 1930).
Similar results were obtained regarding the mech-
anical modulation of the beating pattern in star-
Metachronic wave: A metachronic wave develops when different cilia are beating with a constant phase difference. The ciliary beat consists of a fast effective
stroke during which the cilium moves rapidly in a plane perpendicular to the cell surface and of a recovery stroke during which the cilium returns to the initial
position, moving more slowly in a plane inclined to the cell surface. The movements of the cilia are co-ordinated in time and space with a phase difference
between them to create a wave. This co-ordination is called metachronism or a metachronal wave. This cooperative beating pattern allows the propulsion of
inhaled, mucus-trapped particles out of the lung.
Review
fish sperm flagella. Additionally, it was possible to
change the frequency of the sperm flagellar beating
by applying rhythmic forces with frequencies dif-
ferent from the intrinsic frequency of the flagellum,
employing a micro-needle (Okuno and Hiramoto,
1976). These results suggest that cilia are coupled
to one another through forces applied by the fluid
around them, which allows them to build a meta-
chronic wave, maintaining a constant phase difference
between the oscillators (Tamm et al., 1975). Meta-
chronal waves can propagate in the direction of the
effective stroke (symplectic), in the opposite direc-
tion (antiplectic), perpendicular direction (laeoplectic
or dexioplectic) or oblique direction (Niedermayer
et al., 2008). Prominent examples for such synchron-
ization processes in nature are the adjustment of the
glowing rhythms of huge colonies of fireflies (Buck
and Buck, 1968), the synchronized firing of pace-
maker neurons (Ramirez et al., 2004) or co-ordinated
calcium oscillations in neighbouring muscle cells
(Koenigsberger et al., 2005). Mathematical models
for coupled oscillators, simulating ciliary interac-
tions, have been described and showed that hydro-
dynamic interaction can lead to self-organized, col-
lective ciliary motion, particularly to synchronization
of beating and metachronal wave formation (Guirao
and Joanny, 2007; Niedermayer et al., 2008). Besides
the mathematical models, experimental descriptions
of metachronal waves by simultaneous three-point
measurements have been published (Gheber et al.,
1998). These experiments show that the direction
of the metachronal wave are dependent on the rate of
the ciliary beat as well as on the viscosity of the
surrounding fluid (Gheber et al., 1998). Stimulation
of frog esophagus cilia with ATP or ACh showed
an increased diaplectic co-ordination of the meta-
chronal activity. On the other hand, increasing the
viscosity of the fluid in which cilia were bathed led
to a more orthoplectic movement of the metachronal
wave (Gheber et al., 1998). Both these findings can be
explained by higher asymmetry of the beat at higher
compared to lower frequencies. Interestingly, it has
also been shown that ciliary beating in a metachronal
www.biolcell.org | Volume 103 (4) | Pages 159169 165

wave can beat faster with less use of ATP as compared
with a single cilium (Guirao and Joanny, 2007).
Synchronization of the frequency
For unicellular organisms, integrated control of beat-
ing is reasonably well understood. The ionic fluxes
and electrical signals that are involved in the con-
trol of axonemal activity are quickly and evenly dis-
tributed throughout the cell. Consequently, all cilia
of the cell will have a similar functional status in
terms of beat frequency and orientation. The hy-
drodynamic forces acting between the cilia will en-
courage the formation of metachrony and, hence, ef-
ficiency. By contrast, metazoan systems frequently
consist of many ciliated cells. Thus, conditions that
mediate alterations in axonemal activity must be dis-
tributed throughout the cell as well as communicated
to all neighbouring cells before the system can per-
form efficient adjustments in ciliary behaviour to ac-
commodate environmental changes (Sanderson et al.,
1988). The application of mechanical stimulation as
well as ATP leads to CBF increases in a group of
tracheal cells of rabbits (Evans and Sanderson, 1999;
Sanderson and Dirksen, 1986). Surrounding adjacent
cells displayed a similar frequency response after a
short delay. It has been shown that release of Ca2+ by
IP3 is necessary for the propagation of intercellular
Ca2+ waves and this originally suggested that IP3
moved through gap junctions to communicate inter-
cellular Ca2+ waves (Boitano et al., 1992). However,
recently, a group examined whether there was a dif-
ference between the organization of the intercellular
gap junctions, when airway epithelial cells were cul-
tured on collagen only versus collagen and laminin-
332 (33 2) (Isakson et al., 2006). Interestingly, it
was found that there was a significant increase in in-
tercellular dye transfer in the laminin-treated group,
indicating an increase in gap junctions, but the Ca2+
wave propagation in laminin-treated cells was inde-
pendent of cellcell contact and could be blocked
by apyrase, indicating a role of release of purinergic
substances as part of the calcium wave propagation
(Homolya et al., 2000; Isakson et al., 2006). This pat-
tern of combined signal transmission is in accordance
with a new computer simulation of signal transmis-
sion, where it was shown in a model of a single cell to a
spatial model of a cell culture that the distribution of
Ca2+ was more bell shaped than the flat profile seen
in experimental studies, suggesting a mechanism of
166 
C The Authors Journal compilation 
C 2011 Portland Press Limited
A. Schmid and M. Salathe
regenerative release of ATP from cells downstream
of the stimulated cells (Warren et al., 2010). Addi-
tionally, this pattern of signal propagation has been
proposed for signalling in non-confluent cell cultures
of human bronchial epithelium, where Ca2+ waves
are able to jump over physical gaps (Homolya et al.,
2000).
Airway tasting
Recently, several members of the bitter taste receptor
(T2R) family have been found expressed in differ-
ent epithelia by microarray analysis. Four of these
receptors have also been found on cilia of ciliated
cells in the human airways. Interestingly, a stimula-
tion of these receptors with denatonium (ligand for
T2R4), thujone (ligand for T2R14), salicin (ligand
for T2R16), nicotine and quinine increased intra-
cellular Ca2+ concentrations. Stimulation with de-
natonium led to a CBF increase of approx. 25% (Shah
et al., 2009). These findings indicate that taste recep-
tion may be involved in the increase in mucociliary
clearance.
Conclusions
Calcium is one of the major regulators of ciliary beat
in human airways. Stimulation of purinergic and ACh
receptors leads to locally increased intracellular cal-
cium and thus accelerated ciliary beat. Additionally,
calcium is involved in the co-ordination of the beat-
ing of individual cilia. Altogether, calcium is one of
the major contributors to optimize mucociliary clear-
ance in the human airways.
The understanding of these mechanisms is of ut-
most importance since the treatment of pulmonary
diseases with extensive morbidity and mortality [e.g.
COPD (chronic obstructive pulmonary disease) and
cystic fibrosis] are critically dependent on the optim-
ization of mucociliary clearance mechanisms. Further
research should focus on the understanding of the
effect of Ca2+ at the ciliary axoneme. The particu-
lar composition of the ciliary membrane needs to be
better understood and may harbour new targets for
ciliary beat regulation. Finally, the recent descrip-
tion of bitter taste receptors in ciliated cells opens a
new field of ciliary beat regulation, which has to be
explored. Increased knowledge of all this could lead
to better targeting of the increase and co-ordination
of ciliary beating.
Role of calcium in CBF
Funding
The work of the authors is supported by the National
Institutes of Health, FAMRI and the James and
Esther King Florida Biomedical Research Program.
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