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
Trang 1Synchronization of Ca2+ oscillations: a coupled
oscillator-based mechanism in smooth muscle
Mohammad S Imtiaz1, Pierre-Yves von der Weid1and 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
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
con-tractions 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,
partici-pate 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 oscil-lating 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 contrac-tions The key elements of this mechanism are a
Ca2+ release–refill cycle of endoplasmic reticulum⁄
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: mimtiaz@ucalgary.ca
(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 phe-nomena 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 depolariza-tions that underlie rhythmic contracdepolariza-tions 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
Abbreviations
[Ca 2+ ]c, cytosolic Ca 2+ concentration; 18-b-GA, 18-b-glycyrrhetinic acid; ICC, interstitial cell of Cajal; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate.
Trang 2sarcoplasmic 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
Gastric smooth muscle slow waves
Slow waves are rhythmic electrical depolarizations that
control the mechanical activity of many smooth
mus-cles [1,11–13] (Fig 1) Slow waves cause entry of Ca2+
through opening of L-type Ca2+channels and
contrac-tions 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
syn-cytia have low input impedance, and hence require a
massive amount of current to cause pacemaker
depo-larization On the basis of experimental and theoretical
considerations, we now consider how Ca2+oscillations
can be synchronized across multiple cells in a
syn-cytium
Synchronization of Ca2+oscillations One reported means by which stores achieve local syn-chrony is by Ca2+waves, a significant form of signal-ing in livsignal-ing 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 interac-tions 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 cou-pled oscillators is a group of pendulums that are con-nected 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
simulta-neously recorded at two sites along a
guinea pig gastric smooth muscle tissue
strip before (1), during (2) and after (3)
central application of 60 l M 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 l M ) was present throughout.
Vm= )59 mV Adapted from [8].
Trang 3An experiment that illustrates the underlying
cou-pled 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
mea-sured with two intracellular microelectrodes When the
gap junction blocker 18-b-glycyrrhetinic acid
(18-b-GA; 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
resynchro-nized
What is the mechanism of coupling
Oscillating Ca2+ stores can interact by altering the
phase of adjacent oscillators through Ca2+
-induced-Ca2+ 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
such as Ins(1,4,5)P3, even though the effective diffu-sion of Ins(1,4,5)P3is approximately three times higher than that of Ca2+ [24] However, a candidate mecha-nism that could serve as a coupling spring involves electrical membrane potential changes caused by Ca2+ store-activated inward current flow [5,8,18,25] Electri-cal 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 steady-state 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 cou-pling 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 pre-sented in which caffeine was used to block store Ca2+ release and resulting slow-wave potentials (Fig 2A) Application of the caffeine-containing physiological sal-ine 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
20 mV
10 mV
2 min
F
F0 =1
Ca
3.0 mm 5.0 mm
20 s
B
A
Caffeine
Caffeine
Fig 2 Central interruption of stored Ca 2+ release decouples slow waves (A) Caffeine (0.5 m M ), applied to an Oregon Green-loaded guinea pig gastric smooth muscle tissue strip, blocked slow waves (upper trace) and underlying Ca2+ release-associ-ated increases in [Ca 2+ ]c(lower trace) F0, baseline fluorescence; F, fluorescence;
n F ⁄ 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 applica-tion of 1 m M caffeine applied at widths of 3 and 5 mm The 3 mm stream markedly increased jitter between the delays By con-trast, 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 l M ) was present throughout in (A) and (B) Vm: (A) )56 mV; (B) ) 67 mV Adapted from [8].
Trang 4mediated 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
oscil-lations in stored Ca2+ couple intercellularly across the
syncytial smooth muscle by electrical coupling to
gener-ate 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,
pled oscillator interactions also require chemical
cou-pling, 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
mod-ulate store excitability⁄ oscillations by modulating Ca2+
and⁄ or Ins(1,4,5)P3concentrations 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
syncy-tium, so stores can now interact across cells through
electrical signals; and (e) the effective distance that
Ca2+and Ins(1,4,5)P3can 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 sys-tem is based on gastric smooth muscle, where depolar-ization 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 oscillat-ing, 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 depo-larizes both cells (Fig 4D) Depolarization in cell 2 causes an increase in cytosolic Ins(1,4,5)P3 concen-tration 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 oscil-lations 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
Cytosol-Ca 2+
Ca 2+ St or e
+/ – +/ –
Ins(1,4,5)P3(V) or Ca2+(V)
Local oscillato r
V
AT Pase
Cytosol-Ca 2+
Ca 2+ St or e
oscillato r
V
Ins(1,4,5)
Ins(1,4,5)
AT Pase
Strong electrical couplin g
W eak chemical coupling Gap junction
Ins(1,4,5)P3(V)
or Ca 2+ (V)
Fig 3 A schematic representation of the two-cell system Each cell is a local oscillator composed of a cytosolic store Ca 2+ -excitable sys-tem The cytosolic Ca 2+ of each oscillator is transformed into membrane potential (V) oscillations by a Ca 2+ -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 Ca 2+ influx Ins(1,4,5)P3R, Ins(1,4,5)P3 receptor; ATPase, ATPase pump Adapted from [37].
Trang 5composed of a large number of Ca2+store oscillators.
In this simulation, the intrinsic frequencies of
oscilla-tors 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
tis-sue When gastric smooth muscle is freshly dissected
and isolated, it usually remains quiescent, and
mem-brane potential recordings display a noisy baseline
Confocal Ca2+ imaging records obtained during this
time reveal asynchronous isolated Ca2+events [8]
simi-lar 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)
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 syn-thesis 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 diffu-sion 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 modula-tion 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 synchro-nize 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
0
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P3
] c
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) [Ca 2+ ]cplot of cell 1 and cell 2 before (A) and after (B) coupling (C, E) [Ca 2+ ]cand [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].
Trang 6synchronize Ca2+ oscillations However, their
simula-tion 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
oscil-latory 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
mecha-nism in lymphatic smooth muscle
Lymphatic pacemaking
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 constric-tion and relaxaconstric-tion 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 intra-cellular Ca2+ stores [19] Spontaneous Ca2+ releases from Ins(1,4,5)P3 receptor-operated Ca2+ stores acti-vate 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 underpin-ning vasomotion in both blood and lymphatic vessels [5,6,9] The mechanism operates on the same principles
as outlined for gastrointestinal smooth muscle, but dif-fers from it in that the ‘springs’ that couple the oscilla-tors now rely on voltage coupling mediated by Ca2+ entry through L-type Ca2+ channels rather than volt-age-dependent production of Ins(1,4,5)P3
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 intra-muscularly 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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Time (min) Time (min)
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A
B
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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 l M ) 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
mem-brane potential in (A) (C) When voltage-dependent synthesis of
Ins(1,4,5)P3is 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
parame-ters are the same as in (A) Adapted from [37].
Trang 7operates 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
syn-chronization 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
stom-ach 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
depolariza-tion [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
pro-duce sufficient synchrony to act as a pacemaker
mech-anism 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
accompany-ing review), and it will be interestaccompany-ing to determine the relative role of this mechanism
In summary, store-based pacemaking, whether oper-ated by Ins(1,4,5)P3 receptors or by ryanodine recep-tors, has a role in a range of tissues where cells are electrically connected The key for a functional pace-maker mechanism in such cell syncytia is that oscilla-tory 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]
References
1 Daniel EE, Bardakjian BL, Huizinga JD & Diamant
NE (1994) Relaxation oscillator and core conductor models are needed for understanding of GI electrical activities Am J Physiol 266, G339–349
2 Collins SM (1986) Calcium utilization by dispersed canine gastric smooth muscle cells Am J Physiol 251, G181–188
3 Nakayama S, Shimono K, Liu HN, Jiko H, Katayama
N, Tomita T & Goto K (2006) Pacemaker phase shift
in the absence of neural activity in guinea-pig stomach:
a microelectrode array study J Physiol 576, 727–738
4 van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P-Y & Dosen PJ (2000) Role of calcium stores and membrane voltage in the generation of slow wave action potentials in the guinea-pig gastric pylorus
J Physiol 524, 245–265
5 Peng H, Matchkov V, Ivarsen A, Aalkjaer C & Nilsson
H (2001) Hypothesis for the initiation of vasomotion Circ Res 88, 810–815
6 Koenigsberger M, Sauser R, Lamboley M, Beny JL & Meister JJ (2004) Ca2+ dynamics in a population of smooth muscle cells: modeling the recruitment and synchronization Biophys J 87, 92–104
7 van Helden DF & Imtiaz MS (2003) Ca2+ phase waves emerge Physiol News 52, 7–11
8 van Helden DF & Imtiaz MS (2003) Ca2+ phase waves: a basis for cellular pacemaking and long-range synchronicity in the guinea-pig gastric pylorus J Physiol
548, 271–296
9 Imtiaz MS, Zhao J, Hosaka K, von der Weid PY, Crowe M & van Helden DF (2007) Pacemaking through Ca2+ stores interacting as coupled oscillators via membrane depolarization Biophys J 92, 3843–3861
10 Imtiaz MS, Katnik CP, Smith DW & van Helden DF (2006) Role of voltage-dependent modulation of store Ca2+ release in synchronization of Ca2+ oscillations Biophys J 90, 1–23
Trang 811 Sanders KM (1996) A case for interstitial cells of Cajal
as pacemakers and mediators of neurotransmission in
the gastrointestinal tract Gastroenterology 111, 492–515
12 Exintaris B, Nguyen DT, Lam M & Lang RJ (2009)
Inositol trisphosphate-dependent Ca(2+) stores and
mitochondria modulate slow wave activity arising from
the smooth muscle cells of the guinea pig prostate
gland Br J Pharmacol 156, 1098–1106
13 Hashitani H, van Helden DF & Suzuki H (1996)
Prop-erties of spontaneous depolarizations in circular smooth
muscle cells of rabbit urethra Br J Pharmacol 118,
1627–1632
14 Liu LW, Thuneberg L & Huizinga JD (1995)
Cyclo-piazonic acid, inhibiting the endoplasmic reticulum
calcium pump, reduces the canine colonic pacemaker
frequency J Pharmacol Exp Ther 275, 1058–1068
15 Suzuki H, Takano H, Yamamoto Y, Komuro T, Saito
M, Kato K & Mikoshiba K (2000) Properties of gastric
smooth muscles obtained from mice which lack inositol
trisphosphate receptor J Physiol 525, 105–111
16 Suzuki H & Hirst GD (1999) Regenerative potentials
evoked in circular smooth muscle of the antral region
of guinea-pig stomach J Physiol 517, 563–573
17 Hirst GD, Bramich NJ, Teramoto N, Suzuki H &
Edwards FR (2002) Regenerative component of slow
waves in the guinea-pig gastric antrum involves a
delayed increase in [Ca(2+)](i) and Cl(–) channels
J Physiol 540, 907–919
18 von der Weid PY, Rahman M, Imtiaz MS & van Helden
DF (2008) Spontaneous transient depolarizations in
lym-phatic vessels of the guinea pig mesentery: pharmacology
and implication for spontaneous contractility Am
J Physiol Heart Circ Physiol 295, H1989–2000
19 van Helden DF (1993) Pacemaker potentials in
lympha-tic smooth muscle of the guinea-pig mesentery J
Phys-iol (Lond) 471, 465–479
20 Berridge MJ (1993) Inositol trisphosphate and calcium
signalling Nature 361, 315–325
21 Callamaras N, Marchant JS, Sun XP & Parker I (1998)
Activation and co-ordination of InsP3-mediated
elemen-tary Ca2+ events during global Ca2+ signals in
Xenopus oocytes J Physiol 509, 81–91
22 Kusters JM, van Meerwijk WP, Ypey DL, Theuvenet
AP & Gielen CC (2008) Fast calcium wave propagation
mediated by electrically conducted excitation and
boosted by CICR Am J Physiol Cell Physiol 294,
C917–930
23 Strogatz SH & Stewart I (1993) Coupled oscillators and
biological synchronization Sci Am 269, 102–109
24 Allbritton NL, Meyer T & Stryer L (1992) Range of
messenger action of calcium ion and inositol
1,4,5-tris-phosphate Science 258, 1812–1815
25 Imtiaz MS, Smith DW & van Helden DF (2002) A theoretical model of slow wave regulation using volt-age-dependent synthesis of inositol 1,4,5-trisphosphate Biophys J 83, 1877–1890
26 Hirst GD & Edwards FR (2006) Electrical events underlying organized myogenic contractions of the guinea pig stomach J Physiol 576, 659–665
27 Hirst GD & Ward SM (2003) Interstitial cells: involve-ment in rhythmicity and neural control of gut smooth muscle J Physiol 550, 337–346
28 Komuro T (2006) Structure and organization of intersti-tial cells of Cajal in the gastrointestinal tract J Physiol
576, 653–658
29 Sanders KM & Ward SM (2007) Kit mutants and gas-trointestinal physiology J Physiol 578, 33–42
30 Sergeant GP, Hollywood MA, McCloskey KD, McHale
NG & Thornbury KD (2001) Role of IP(3) in modula-tion of spontaneous activity in pacemaker cells of rabbit urethra Am J Physiol Cell Physiol 280, C1349–1356
31 Maltsev VA & Lakatta EG (2009) Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function
in a novel pacemaker cell model Am J Physiol Heart Circ Physiol 296, H594–615
32 Lakatta EG, Vinogradova T, Lyashkov A, Sirenko S, Zhu W, Ruknudin A & Maltsev VA (2006) The integra-tion of spontaneous intracellular Ca2+ cycling and surface membrane ion channel activation entrains normal automaticity in cells of the heart’s pacemaker Ann NY Acad Sci 1080, 178–206
33 Eisner DA, Kashimura T, Venetucci LA & Trafford
AW (2009) From the ryanodine receptor to cardiac arrhythmias Circ J 73, 1561–1567
34 Eisner DA, Kashimura T, O’Neill SC, Venetucci LA & Trafford AW (2009) What role does modulation of the ryanodine receptor play in cardiac inotropy and arrhythmogenesis? J Mol Cell Cardiol 46, 474–481
35 Beckett EA, Bayguinov YR, Sanders KM, Ward SM & Hirst GD (2004) Properties of unitary potentials gener-ated by intramuscular interstitial cells of Cajal in the murine and guinea-pig gastric fundus J Physiol 559, 259–269
36 Yamashita M, Sugioka M & Ogawa Y (2006) Voltage-and Ca2+-activated potassium channels in Ca2+ store control Ca2+ release FEBS J 273, 3585–3597
37 Imtiaz MS (2003) Distributed Pacemaking through
Long-range Signaling in Smooth Muscle University of Newcastle, Newcastle, Australia