MINIREVIEW
Synchronization of Ca2+ oscillations: a coupled
oscillator-based mechanism in smooth muscle
Mohammad S. Imtiaz1, Pierre-Yves von der Weid1 and Dirk F. van Helden2
1 Department of Physiology and Pharmacology, University of Calgary, Alberta, Canada
2 School of Biomedical Sciences, University of Newcastle, Callaghan, NSW, Australia
Keywords
Ca2+ oscillations; Ca2+ stores; coupled
oscillators; lymphatics; slow waves;
synchronization
Correspondence
M. S. Imtiaz, Department of Physiology &
Pharmacology, Faculty of Medicine,
University of Calgary, Health Sciences
Centre, 3330 Hospital Drive NW, Calgary,
Alberta T2N 4N1, Canada
Fax: +1 403 210 8195
Tel: +1 403 210 9838
E-mail: [email protected]
(Received 31 March 2009, revised
11 September 2009, accepted 14
October 2009)
doi:10.1111/j.1742-4658.2009.07437.x
Entrained oscillations in Ca2+ underlie many biological pacemaking phenomena. In this article, we review a long-range signaling mechanism in
smooth muscle that results in global outcomes of local interactions. Our
results are derived from studies of the following: (a) slow-wave depolarizations that underlie rhythmic contractions of gastric smooth muscle; and (b)
membrane depolarizations that drive rhythmic contractions of lymphatic
smooth muscle. The main feature of this signaling mechanism is a coupled
oscillator-based synchronization of Ca2+ oscillations across cells that
drives membrane potential changes and causes coordinated contractions.
The key elements of this mechanism are as follows: (a) the Ca2+ release–
refill cycle of endoplasmic reticulum Ca2+ stores; (b) Ca2+-dependent
modulation of membrane currents; (c) voltage-dependent modulation of
Ca2+ store release; and (d) cell–cell coupling through gap junctions or
other mechanisms. In this mechanism, Ca2+ stores alter the frequency of
adjacent stores through voltage-dependent modulation of store release.
This electrochemical coupling is many orders of magnitude stronger than
the coupling through diffusion of Ca2+ or inositol 1,4,5-trisphosphate, and
thus provides an effective means of long-range signaling.
Long-range signaling
Biological organs display coordinated activities that
can extend over large distances. The spatial extent of
signaling required for such long-distance coordination
is many orders of magnitude greater than the size of
the participating cells; for example, coordinated contractions of the intestine can occur over 250 cm
lengths [1], whereas smooth muscle cells are small
(typical size range 50–200 lm [2]). The problem is
further exacerbated when one considers that millions
of cells, each with its own intrinsic rhythm, participate in this ‘mob action’, and yet a meaningful global
outcome emerges. It is fascinating that in systems
such as the gut, even isolated muscle tissue
preparations continue to show coordinated rhythmic
contractions in the absence of any external neural
control [3]; thus, in such systems, the synchronizing
mechanism is embedded within the rhythmically oscillating cells themselves. In this article, we review a
long-range signaling mechanism in smooth muscle
that explains global outcomes of local interactions [4–
10]. The main feature of this signaling mechanism is
coupled oscillator-based synchronization of Ca2+
oscillations across cells, which drives membrane
potential changes and causes coordinated contractions. The key elements of this mechanism are a
Ca2+ release–refill cycle of endoplasmic reticulum ⁄
Abbreviations
[Ca2+]c, cytosolic Ca2+ concentration; 18-b-GA, 18-b-glycyrrhetinic acid; ICC, interstitial cell of Cajal; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate.
278
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M. S. Imtiaz et al.
sarcoplasmic reticulum Ca2+ stores, Ca2+-dependent
modulation of membrane currents, voltage-dependent
modulation of store release, and cell–cell coupling
through gap junctions or other mechanisms.
Ca2+ store-based pacemaking
Gastric smooth muscle slow waves
Slow waves are rhythmic electrical depolarizations that
control the mechanical activity of many smooth muscles [1,11–13] (Fig. 1). Slow waves cause entry of Ca2+
through opening of L-type Ca2+ channels and contractions of the smooth muscle. Cyclical release of Ca2+
from inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-sensitive
endoplasmic Ca2+ stores underlies the generation of
slow waves [12–15]. The store-generated change in
cytosolic Ca2+ concentration ([Ca2+]c) causes opening
of excitatory channels, which allows inward current
flow and generates rhythmic pacemaker depolarization
[4,16–18]. However, the difficulty with oscillatory
Ca2+ release providing a pacemaker mechanism is that
it requires synchronization of large numbers of stores
across many cells [4,19]. Gastric smooth muscle cells
and associated interstitial cells of Cajal (ICCs) form a
syncytium interconnected by gap junctions. Such syncytia have low input impedance, and hence require a
massive amount of current to cause pacemaker depolarization. On the basis of experimental and theoretical
considerations, we now consider how Ca2+ oscillations
can be synchronized across multiple cells in a syncytium.
Synchronization by voltage-modulated store release
Synchronization of Ca2+ oscillations
One reported means by which stores achieve local synchrony is by Ca2+ waves, a significant form of signaling in living organisms [20–22]. Ca2+ waves are
considered to be generated by the release of Ca2+
from a dominant store, triggering Ca2+-induced Ca2+
release from adjacent stores, and the continuation of
this process along the array of stores. However, Ca2+
waves propagate relatively slowly, typically at
< 0.1 mmÆs)1. Thus, Ca2+ waves cannot explain the
synchrony of Ca2+ oscillations underlying slow waves,
which appear to be conducted at velocities of many
millimeters per second.
Coupled oscillators
Another means by which stores can synchronize their
Ca2+ release cycle is by coupled oscillator-based interactions. The theory of coupled oscillators emerged from a
fortuitous observation of pendulum clocks by the Dutch
physicist Christiaan Huygens [23]. He noted that clock
pendulums could synchronize their oscillations even
though they were separated by distances of meters. This
synchronization of clock pendulums occurred through
coupling between the pendulums by transmission of
minute vibrations through the wall. An example of coupled oscillators is a group of pendulums that are connected to each other by springs. When all pendulums
are randomly set to swing, over time, interactions
through the springs result in the appearance of a global
synchrony pattern involving all the pendulums.
Fig. 1. Central interruption of intercellular
connectivity decouples slow waves.
Pacemaker potentials ⁄ slow waves simultaneously recorded at two sites along a
guinea pig gastric smooth muscle tissue
strip before (1), during (2) and after (3)
central application of 60 lM 18-b-GA.
Decoupling commenced 1.5 min after
application of the blocker and was not
phase-locked, as more slow waves occurred
at site 2 than at site 1. For example, upon
commencement of decoupling, four slow
waves occurred at site 1 and five at site 2,
with delays between the slow waves
(site 2 ) site 1) of 0.8, 3.2, 7.9 and 9.5 s for
the first five sequential slow waves.
Nifedipine (1 lM) was present throughout.
Vm = )59 mV. Adapted from [8].
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M. S. Imtiaz et al.
An experiment that illustrates the underlying coupled oscillator nature of slow waves involved a single
bundle strip of circular smooth muscle dissected from
the guinea pig gastric pylorus (Fig. 1). Initially, slow
waves occurred synchronously in the strip, as measured with two intracellular microelectrodes. When the
gap junction blocker 18-b-glycyrrhetinic acid (18-bGA; 40 mm) was applied centrally in a narrow stream
approximately 0.5 mm wide to this strip, slow waves
recorded at the two electrodes continued to occur but
were no longer synchronized. When 18-b-GA was
removed, slow waves in the two regions resynchronized.
such as Ins(1,4,5)P3, even though the effective diffusion of Ins(1,4,5)P3 is approximately three times higher
than that of Ca2+ [24]. However, a candidate mechanism that could serve as a coupling spring involves
electrical membrane potential changes caused by Ca2+
store-activated inward current flow [5,8,18,25]. Electrical coupling can be 100–1000 times stronger than
chemical coupling, as the electrical length constant of
smooth muscle (i.e. the distance needed for a steadystate voltage resulting from current injection to
decrease to 37% of its original size) is typically in
the range 2–3 mm [26].
Finding experimental evidence that electrical coupling is the key ‘spring’ interlinking the Ca2+ stores
has involved repeating the decoupling experiment of
Fig. 1, but inhibiting the oscillators (i.e. the Ca2+
stores) while leaving the connectivity between cells
intact [8]. An example of such an experiment is presented in which caffeine was used to block store Ca2+
release and resulting slow-wave potentials (Fig. 2A).
Application of the caffeine-containing physiological saline solution to the central region of a single bundle
strip of guinea pig gastric circular smooth muscle
caused decoupling when the store inhibitor was applied
in a very wide stream about 5 mm in width, but not
when the stream was narrower (e.g. 3 mm; Fig. 2B).
These distances are commensurate with coupling being
What is the mechanism of coupling
between Ca2+ stores?
Oscillating Ca2+ stores can interact by altering the
phase of adjacent oscillators through Ca2+-inducedCa2+ release. Here, coupling by exchange of Ca2+
[and ⁄ or Ins(1,4,5)P3 for Ins(1,4,5)P3 receptor-operated
stores] through gap junctions could serve as the spring
joining the pendulums in the above analogy. However,
coupling through release of Ca2+ results in very weak
coupling, as the effective diffusion of Ca2+ is limited
to very short distances ( 5 lm) [24]. The same applies
to coupling through diffusion of second messengers
Caffeine
A
20 mV
F =1
F0
Ca
2 min
el2
el1
B
Caffeine
Control
3.0 mm
5.0 mm
Control
10 mV
20 s
280
Fig. 2. Central interruption of stored Ca2+
release decouples slow waves. (A) Caffeine
(0.5 mM), applied to an Oregon Greenloaded guinea pig gastric smooth muscle
tissue strip, blocked slow waves (upper
trace) and underlying Ca2+ release-associated increases in [Ca2+]c (lower trace). F0,
baseline fluorescence; F, fluorescence;
nF ⁄ F0, relative change in fluorescence
normalized to baseline. (B) Slow waves
recorded at two sites 6 mm apart along a
strip before, during and after central application of 1 mM caffeine applied at widths of 3
and 5 mm. The 3 mm stream markedly
increased jitter between the delays. By contrast, the 5 mm stream decoupled the slow
waves. Decoupling commenced 1 min
after application of the blocker and was not
phase-locked, with slow waves at the two
recording sites now occurring at significantly
different frequencies (P < 0.05; frequencies
3.7 ± 0.1 per min and 4.4 ± 0.1 per min at
electrodes 1 and 2, respectively; n = 10).
Nifedipine (1 lM) was present throughout in
(A) and (B). Vm: (A) )56 mV; (B) ) 67 mV.
Adapted from [8].
FEBS Journal 277 (2010) 278–285 ª 2009 The Authors Journal compilation ª 2009 FEBS
M. S. Imtiaz et al.
Synchronization by voltage-modulated store release
mediated by intercellular current flow in these strips,
which exhibited a length constant of about 3 mm. This
and related experiments [8] fit the hypothesis that oscillations in stored Ca2+ couple intercellularly across the
syncytial smooth muscle by electrical coupling to generate highly synchronous slow waves.
Modeling studies
As considered above, electrical conduction is many
orders of magnitude stronger than chemical coupling,
and this provides the ‘spring’ that underlies entrainment
of Ca2+ stores to pace tissue syncytia. However, coupled oscillator interactions also require chemical coupling, in that store-generated changes in [Ca2+]c are
required to activate inward membrane current, with the
resulting membrane depolarization activating or
advancing the phase of other Ca2+stores. The electrical
and chemical transduction pathways are as depicted in
Fig. 3. The key mechanisms are as follows: (a) cyclical
release of Ca2+ from stores can occur spontaneously
and is modulated by two signals – Ca2+ and
Ins(1,4,5)P3; (b) release of Ca2+ from stores activates
an inward current and depolarizes the membrane [18] –
thus, store oscillations are transformed into membrane
potential oscillations; (c) membrane potential can modulate store excitability ⁄ oscillations by modulating Ca2+
and ⁄ or Ins(1,4,5)P3 concentrations in the cytosol – this
provides a pathway for transforming electrical signals
into chemical signals to which the stores respond; (d)
cells are connected by gap junctions and form a syncytium, so stores can now interact across cells through
electrical signals; and (e) the effective distance that
Ca2+ and Ins(1,4,5)P3 can diffuse is very short, in the
low micrometer range, whereas electrical coupling is in
the order of millimeters – thus, whereas stores are
weakly coupled through chemical diffusion, they are
strongly interconnected by electrical coupling.
We now illustrate the coupling mechanism outlined
above with a two-cell model example (Fig. 4). This system is based on gastric smooth muscle, where depolarization of the membrane is modeled to cause an
increase in Ins(1,4,5)P3 concentration in the cytosol
[25]. Cytosolic Ca2+ concentrations of two uncoupled
model cells are shown in Fig. 4A. Cell 1 (solid line) is
more sensitive to Ins(1,4,5)P3, and is therefore oscillating, whereas cell 2 (dashed line) is quiescent, because it
is less sensitive to Ins(1,4,5)P3. Electrical coupling is
then instituted between the two cells, and because of
voltage coupling-based interactions, cell 2 begins to
oscillate (Fig. 4B). This occurs because the oscillatory
Ca2+ release from cell 1 (Fig. 4C) activates an inward
current, which, owing to electrical coupling, now depolarizes both cells (Fig. 4D). Depolarization in cell 2
causes an increase in cytosolic Ins(1,4,5)P3 concentration through voltage-dependent activation of
Ins(1,4,5)P3 (Fig. 3), with the increased cytosolic
Ins(1,4,5)P3 concentration causing generation of oscillations in cell 2. Importantly, although the frequency
of the oscillations in cell 2 might be different to that of
cell 1, coupled oscillator interactions advance or retard
the cycle of each cell so that they remain entrained.
Chemical versus electrochemical
coupling
A similar sequence of events occurs when the above
example of two oscillators is extended to a system
V
V
Strong electrical coupling
Ins(1,4,5)P3(V) or Ca2+(V) Ca2+
Weak chemical coupling
Cytosol-Ca2+
+/–
ATPase
Local
oscillator
Ca2+ Store
Ins(1,4,5)P3(V)
or Ca2+(V)
Ins(1,4,5)
P3R
2+
Cytosol-Ca2+
Gap junction
+/–
Ca
+/–
ATPase
Local
oscillator
Ca2+ Store
+/–
Ins(1,4,5)
P3R
Fig. 3. A schematic representation of the two-cell system. Each cell is a local oscillator composed of a cytosolic store Ca2+-excitable system. The cytosolic Ca2+ of each oscillator is transformed into membrane potential (V) oscillations by a Ca2+-activated inward current. The
membrane potentials of the cells are strongly linked. Each local oscillator is weakly linked to the membrane potential by a voltage-dependent
feedback loop such as voltage-dependent Ins(1,4,5)P3 synthesis or voltage-dependent Ca2+ influx. Ins(1,4,5)P3R, Ins(1,4,5)P3 receptor;
ATPase, ATPase pump. Adapted from [37].
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Synchronization by voltage-modulated store release
M. S. Imtiaz et al.
Gap junction
A
Cell 1
B
Cell 2
Cell 1
2+
Cell 2
1
0
40
Cell 2
3
[Ca ]c, Z (µM)
2+
[Ca ]c, Z (µM)
3
2
Gap junction
Cell 1
42
44
46
Time (min)
48
2
1
0
140
50
142
144
146
Time (min)
148
150
2
1.5
1
2+
[Ca ]c, Z (µM)
C
0.5
141
142
143
144
145
146
147
145
146
147
145
146
147
Time (min)
V (mV)
D
–40
–50
–60
[Ins(1,4,5)P3]c, (µM)
–70
141
142
143
144
Time (min)
E
0.35
0.3
0.25
141
142
143
144
Time (min)
Fig. 4. Synchronization of a cell pair. A two-cell system shows how synchrony can be achieved through voltage-dependent modulation of
store release. (A, B) [Ca2+]c plot of cell 1 and cell 2 before (A) and after (B) coupling. (C, E) [Ca2+]c and [Ins(1,4,5)P3]c, respectively, for the
two cells after they are coupled. Note that the membrane potentials (D) for both cells are same, owing to large electrical coupling. Note that
changes in [Ins(1,4,5)P3]c for both cells follow changes in the membrane potential. Adapted from [10].
composed of a large number of Ca2+ store oscillators.
In this simulation, the intrinsic frequencies of oscillators are different from each other, and as the
[Ins(1,4,5)P3] is increased in the model tissue, a global
synchronous rhythm emerges following events that
grow from a noisy baseline (Fig. 5A).
The above simulation outcome is very similar to
what is observed in isolated gastric smooth muscle tissue. When gastric smooth muscle is freshly dissected
and isolated, it usually remains quiescent, and membrane potential recordings display a noisy baseline.
Confocal Ca2+ imaging records obtained during this
time reveal asynchronous isolated Ca2+ events [8] similar to those seen in the simulated voltage recordings of
Fig. 5B1. However, over time, these release events
begin to synchronize and summate to larger events
(Fig. 5B2), and finally a global synchronous rhythm
emerges (Fig. 5B3).
282
We tested the potency of electrochemical coupling
by running the same simulation but allowing no
voltage-dependent modulation of Ca2+ store release.
This was achieved by blocking voltage-dependent synthesis of Ins(1,4,5)P3. In this case, no global synchrony
emerged, and the baseline remained noisy even though
the cells were coupled both electrically and by diffusion of Ca2+ and Ins(1,4,5)P3 (chemical coupling). In
fact, the outcome was very similar to what is seen
when no coupling exists between the cells (achieved by
deleting gap junctions in the simulation) [8,10]. This
example indicates that: (a) voltage-dependent modulation of store release in electrically coupled cells is a
very efficient long-range coupling mechanism; and (b)
chemical coupling by itself is not sufficient to synchronize Ca2+ release events. In this regard, we note that a
modeling study by Koenigsberger et al. [6] showed that
diffusive coupling through Ca2+ is sufficient to
FEBS Journal 277 (2010) 278–285 ª 2009 The Authors Journal compilation ª 2009 FEBS
M. S. Imtiaz et al.
V (mV)
A
Synchronization by voltage-modulated store release
Lymphatic pacemaking
–45
–50
–55
–60
–65
1
0
20
40
2
3
60
80
100 120
Time (min)
140
160
180
3
B
2
1
2 min
2
1
3
20 mV
10 s
V (mV)
C
–55
–60
–65
50
V (mV)
D
100
150
200
Time (min)
250
300
–62
–64
–66
0
20
40
60
80 100 120
Time (min)
140
160
180
Fig. 5. Synchronization of a cell population. (A) The emergence of
synchronized global slow waves in a gap junction-coupled model
cell syncytium. (B) The emergence of slow waves in guinea pig
pyloric smooth muscle. Nifedipine (1 lM) was present throughout.
The voltage scale bar applies to all records. Events marked with
labeled arrows are shown on an expanded time scale. The resting
membrane potential was )59 mV. Expanded regions 1, 2 and 3 are
similar to events similarly marked in the model syncytium membrane potential in (A). (C) When voltage-dependent synthesis of
Ins(1,4,5)P3 is blocked, no synchronous events arise in the model
syncytium, even though all of the other parameters are the same
as in (A). (D) Similarly, no synchronous events arise if gap junctions
are blocked in the model syncytium, even though all the parameters are the same as in (A). Adapted from [37].
synchronize Ca2+ oscillations. However, their simulation entailed only a small number of cells. Our findings
agree with those of Koenigsberger et al. for the case of
a small number of cells that have similar intrinsic oscillatory frequencies and that are not separated by large
distances, but their results do not apply to long-range
coupling involving large numbers of cells.
The electrochemical coupling of intracellular stores
is found, with variations, in other systems as well.
Below, we present some details that illustrate the same
principles of pacemaking and synchronization mechanism in lymphatic smooth muscle.
A rhythmic constriction–relaxation cycle is displayed
by blood and lymphatic vessels, a phenomenon known
as vasomotion. Lymphatic vessels are divided into
chambers by interconnecting valves. Rhythmic constriction and relaxation of these chambers propels lymph
fluid through the lymphatic vessels. The pacemaking
mechanism underlying contractions of lymphatic
smooth muscle has been found to be dependent on
Ins(1,4,5)P3-receptor operated Ca2+ release from intracellular Ca2+ stores [19]. Spontaneous Ca2+ releases
from Ins(1,4,5)P3 receptor-operated Ca2+ stores activate a transient inward current, causing a spontaneous
transient depolarization. However, the amount of Ca2+
released from individual or small groups of stores
is small, and results in spontaneous transient
depolarizations that do not reach the threshold for
opening L-type Ca2+ channels which underlie action
potential and constriction. This mechanism can only be
effective if there are cooperative interactions between
the release cycles of the Ca2+ stores, as would be
effected by stores interacting as coupled oscillators [4].
Indeed, this is highly likely to be the situation underpinning vasomotion in both blood and lymphatic vessels
[5,6,9]. The mechanism operates on the same principles
as outlined for gastrointestinal smooth muscle, but differs from it in that the ‘springs’ that couple the oscillators now rely on voltage coupling mediated by Ca2+
entry through L-type Ca2+ channels rather than voltage-dependent production of Ins(1,4,5)P3.
Ca2+ oscillations in other cell types
Gastrointestinal store-based pacemaker activity is, in
fact, more complicated than considered so far, in that
the pacemaker cells driving the slow waves are the
ICCs [27–29]. These cells form networks in regions
such as the myenteric plexus (i.e. ICC-MY) and intramuscularly within the smooth muscle (i.e. ICC-IM),
interconnecting with each other and with adjacent
smooth muscle. As a consequence, the dominant Ca2+
stores that underlie pacemaking reside in these cells
[8,14]. However, whether this is the case may depend
on the tissue. For example, the pacemaker activity that
generates vasomotion in blood and lymphatic vessels,
although Ca2+ store-based, may be driven by Ca2+
stores in the smooth muscle, as a role for ICC-like
cells has yet to be confirmed [5,9,19]. In contrast,
Ca2+ store-based pacemaking in the rabbit urethra is
generated in ICC-like cells [13,30].
There is now evidence that sinoatrial cells that pace
the heart also show Ca2+ store-based oscillation. This
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M. S. Imtiaz et al.
operates together with the classic membrane oscillator
generated by voltage-dependent channels in the cell
membrane to drive the heart [31,32]. It differs from
the smooth muscle cell store oscillator in that it
utilizes ryanodine receptor-operated rather than
Ins(1,4,5)P3 receptor-operated Ca2+ stores. It remains
to be seen whether Ca2+ stores have a role in the synchronization of sinoatrial nodal cells. However, in the
heart muscle, increased Ca2+ store excitability can
cause the emergence of unwanted pacemakers that
result in pathological waves of contractions known as
arrhythmias [33,34]. Indeed, this raises the question of
why stores in the atrial and ventricular muscle do not
normally synchronize, as they do in the pacemaker
node. This is, of course, a very important feature of
the heart, as otherwise the muscle systems themselves
would have autonomous pacemaker capability. The
reason for this needs to be explored, but there is a
very interesting analogous circumstance in the stomach. Here, only the middle and lower sections of the
stomach exhibit slow waves and associated rhythmic
contractions; the upper region of the stomach (i.e. the
gastric fundus) is nonrhythmic. As has been noted,
slow waves are generated by stored Ca2+ release [14],
a mechanism that requires long-range intercellular
synchronization of oscillatory stored Ca2+ release [8].
The gastric fundus should exhibit slow waves, as it
has abundant pacemaker cells (i.e. ICCs) that exhibit
store Ca2+ release coupled to membrane depolarization [35]. However, coupling does not happen! The
reason for this is that stores in this region lack a key
component of their coupling mechanism, namely the
feedback by which membrane depolarization causes
stored Ca2+ release [35]. The consequence is that the
coupling link that allows long-range store coupling is
no longer functional, and hence store pacemaking
cannot occur in this smooth muscle.
Conclusion and future directions
In this article, we have reviewed long-range signaling
through Ca2+ release from intracellular Ca2+ stores,
which is a key determinant of whether stores can produce sufficient synchrony to act as a pacemaker mechanism. Voltage-dependent coupling between Ca2+
stores is critical for such signaling, as it is several
orders of magnitude stronger than chemical coupling
through diffusion of Ca2+ and ⁄ or Ins(1,4,5)P3. In our
model, electrochemical coupling was considered to
occur by intercellular current flow through presumed
gap junctions. However, such electrical coupling could
also occur wholly or in part by capacitive coupling, as
shown in the study of Yamashita [36] (see accompany284
ing review), and it will be interesting to determine the
relative role of this mechanism.
In summary, store-based pacemaking, whether operated by Ins(1,4,5)P3 receptors or by ryanodine receptors, has a role in a range of tissues where cells are
electrically connected. The key for a functional pacemaker mechanism in such cell syncytia is that oscillatory store Ca2+ release generates inward currents and
resultant depolarization, that the cellular network
readily conducts currents, and that the conducted
depolarization in turn leads to activation of other
Ca2+ stores. This latter step could be mediated by
depolarization-induced Ca2+ entry and ⁄ or production
of Ins(1,4,5)P3 [9,25].
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