Tài liệu Báo cáo khoa học: Synchronization of Ca2+ oscillations: a capacitative (AC) electrical coupling model in neuroepithelium pptx

MINIREVIEW
Synchronization of Ca
2+
oscillations: a capacitative (AC)
electrical coupling model in neuroepithelium
Masayuki Yamashita
Department of Physiology I, Nara Medical University, Kashihara, Japan
Structural organization of intracellular
Ca
2+
stores and coupling modes
of Ca
2+
increase
Chemical coupling and DC electrical coupling
The lumen of the endoplasmic reticulum (ER) is
continuous with a space between the outer nuclear
membrane (ONM) and inner nuclear membrane
(INM) [1–3]. Intracellular Ca
2+
stores are formed
within the ER lumen and the space between the ONM
and the INM [1,2]. In cells with a centralized nucleus
surrounded by the ER (Fig. 1A), intercellular commu-
nication may be mediated by the release of a transmit-
Keywords
Ca
2+
oscillation; Ca
2+
store; neuronal

development; synchronization; voltage
fluctuation
Correspondence
M. Yamashita, Department of Physiology I,
Nara Medical University, Shijo-cho 840,
Kashihara 634-8521, Japan
Fax: +81 744 29 0306
Tel: +81 744 29 8827
E-mail:
(Received 23 March 2009, revised 2
October 2009, accepted 9 October
2009)
doi:10.1111/j.1742-4658.2009.07439.x
Increases in intracellular [Ca
2+
] occur synchronously between cells in the
neuroepithelium. If neuroepithelial cells were capable of generating action
potentials synchronized by gap junctions (direct current electrical coupling),
the influx of Ca
2+
through voltage-activated Ca
2+
channels would lead to
a synchronous increase in intracellular [Ca
2+
]. However, no action poten-
tial is generated in neuroepithelial cells, and the [Ca
2+
] increase is instead
produced by the release of Ca

2+
from intracellular Ca
2+
stores. Recently,
synchronous fluctuations in the membrane potential of Ca
2+
stores were
recorded using an organelle-specific voltage-sensitive dye. On the basis of
these recordings, a capacitative [alternating current (AC)] electrical cou-
pling model for the synchronization of voltage fluctuations of Ca
2+
store
potential was proposed [Yamashita M (2006) FEBS Lett 580, 4979–4983;
Yamashita M (2008) FEBS J 275, 4022–4032]. Ca
2+
efflux from the Ca
2+
store and K
+
counterinflux into the store cause alternating voltage changes
across the store membrane, and the voltage fluctuation induces ACs. In
cases where the store membrane is closely apposed to the plasma mem-
brane and the cells are tightly packed, which is true of neuroepithelial cells,
the voltage fluctuation of the store membrane is synchronized between the
cells by the AC currents through the series capacitance of these mem-
branes. This article provides a short review of the model and its relation-
ship to the structural organization of the Ca
2+
store. This is followed by a
discussion of how the mode of synchronization of [Ca

2+
] increase may
change during central nervous system development and new molecular
insights into the synchronicity of [Ca
2+
] increase.
Abbreviations
AC, alternating current; BK channel, big K
+
channel; CNS, central nervous system; DC, direct current; DiOC
5
(3), 3,3¢-dipentyloxacarbocyanine
iodide; ER, endoplasmic reticulum; I
C
, capacitative current; INM, inner nuclear membrane; Ins(1,4,5)P
3
, inositol 1,4,5-trisphosphate; mAChR,
muscarinic acetylcholine receptor; ONM, outer nuclear membrane; Pyk2, proline-rich tyrosine kinase 2; RGC, retinal ganglion cell.
FEBS Journal 277 (2010) 293–299 ª 2009 The Author Journal compilation ª 2009 FEBS 293
ter (e.g. ATP) and its receptors, which stimulate the
release of Ca
2+
from intracellular Ca
2+
stores (Fig. 1B
and Koizumi in this minireview series). This mode of
coupling is referred to as chemical coupling. When gap
junctions are present between adjacent cells, electrical
coupling through gap junction channels may synchro-
nize plasma membrane potentials, and Ca

2+
influx
through voltage-activated Ca
2+
channels should lead
to a synchronous increase in intracellular [Ca
2+
]
(Fig. 1B and Imtiaz et al. in this minireview series).
This coupling mode is mediated by direct currents
(DCs) through gap junction channels, and may be
called DC electrical coupling.
Alternatively, a second messenger molecule such as
inositol 1,4,5-trisphosphate [Ins(1,4,5)P
3
] and ⁄ or Ca
2+
ions may pass gap junction channels, and such pas-
sive diffusion might lead to a synchronous increase in
intracellular [Ca
2+
]. However, the results of our stud-
ies on the retinal neuroepithelium contradict this dif-
fusion model and provide evidence for an alternative
model. We have found that Ins(1,4,5)P
3
-mediated
robust Ca
2+
increases induced by a supramaximal

amount of an agonist do not synchronize, despite
strong gap junctional coupling in the retinal neuroepi-
thelium [4,5]. It has also been shown that synchro-
nous Ca
2+
oscillations occur in newborn retinal
ganglion cells (RGCs), which lose gap junctions [5].
On the basis of these findings, an alternative model
to the passive diffusion of Ins(1,4,5)P
3
or Ca
2+
through gap junction channels is provided to explain
the synchronization of Ca
2+
oscillation between these
cells.
AB
CD
Fig. 1. Structure of intracellular Ca
2+
stores and coupling modes of intracellular [Ca
2+
] increase. (A) Cells in which the nucleus is located in
the center of the cell and is surrounded by ER. Modified from Fig. 1 in [1] with permission. (B) Chemical coupling and DC electrical coupling.
Stored Ca
2+
ions are released by the activation of receptors by a transmitter, such as ATP (chemical coupling). Depolarization (DV) synchro-
nized by gap junctional coupling activates voltage-dependent Ca
2+

channels to cause synchronous Ca
2+
influx (DC electrical coupling). The
Ca
2+
influx may cause Ca
2+
-induced Ca
2+
release to amplify the [Ca
2+
] increase. (C) Neuroepithelial cells in which the ONM is closely
apposed to the plasma membrane (PM) and the cells are tightly packed in the basal layer. Modified from Fig. 2 in [6]. (D) Capacitative (AC)
electrical coupling. Efflux of Ca
2+
from Ca
2+
stores and counterinflux of K
+
cause fluctuations in the membrane potential of the Ca
2+
store,
inducing ACs, which can pass the membranes as capacitative currents (I
C
). The current loop is closed via cytoplasm and the PM or gap junc-
tion (GJ), and also via the extracellular space, even in the absence of GJs. NPC, nuclear pore complex; Nu, nucleoplasm.
Capacitative electrical coupling of Ca
2+
release M. Yamashita
294 FEBS Journal 277 (2010) 293–299 ª 2009 The Author Journal compilation ª 2009 FEBS

Capacitative [alternating current (AC)] electrical
coupling
A novel mechanism of coupling between cells that does
not depend on gap junctions or transmitters has been
proposed, on the basis of the observation that the
membrane potential of Ca
2+
stores oscillates synchro-
nously between cells in the retinal neuroepithelium
[4,6]. The voltage change exhibited a bistable alteration
of fast rising and fast falling, which oscillated at the
same frequency as the Ca
2+
oscillations [4]. The volt-
age change was recorded using an organelle-specific,
voltage-sensitive fluorescent dye, 3,3¢-dipentyloxacarbo-
cyanine iodide [DiOC
5
(3)], and a highly sensitive video
camera, which was connected to a high-speed confocal
scanner (Nipkow disk type) [4]. When the voltage
change was recorded using a photomultiplier, it was
found, surprisingly, that the bistable voltage alteration
consisted of periodic repeats of a burst of high fre-
quency (> 200 Hz) voltage fluctuations [5]. The low
time resolution of the video camera (15 images per sec-
ond) did cover the high-frequency voltage fluctuation.
To explain the synchronization of the store poten-
tial, a capacitative (AC) electrical coupling model has
been proposed, because the fast voltage change across

the store membrane produces ACs, which can pass the
plasma membrane capacitatively when the store mem-
brane is in close proximity to the plasma membrane.
The neuroepithelium consists of bipolar cells, in which
the nuclei are positioned at different levels (pseudostr-
atified columnar epithelium). In the retinal neuroepi-
thelium, the ONM is closely apposed to the plasma
membrane, and the cells are tightly packed in the basal
layer (Fig. 1C). The voltage fluctuations of the Ca
2+
store will induce ACs, which can pass the series capaci-
tance of the ONM and the plasma membrane as capa-
citative currents (I
C
in Fig. 1D). The AC could
synchronize the voltage fluctuations of the Ca
2+
store
between the cells by capacitative (AC) electrical
coupling [5].
The cytoplasm and the plasma membrane will make
a closed-current loop of I
C
(Fig. 1D). Gap junctions
may also contribute to the formation of the current
loop. Another path for I
C
is the extracellular space,
because I
C

can pass the plasma membrane capacita-
tively. Thus, the current loop can be closed via the
extracellular space and the plasma membrane. This
may allow capacitative electrical coupling between
neuroepithelial cells and newborn RGCs, which lack
gap junctions (Fig. 1D). The electrical circuits of the
current loop are presented in Doc. S2 of [5].
The fluctuation in the membrane potential of the
Ca
2+
store may be due to the movement of Ca
2+
ions
and the concomitant movement of other ions across
the store membrane. The Ca
2+
efflux causes a negative
change in the store potential towards the equilibrium
potential of Ca
2+
(lumen-negative), which in turn
induces a counterinflux of K
+
ions to depolarize the
store potential, unless a [K
+
] gradient is formed across
the store membrane. Efflux of Cl
)
or influx of Mg

2+
may also contribute to the depolarization of the store
potential. The depolarization provides the driving force
for Ca
2+
efflux, and the Ca
2+
release may also be
enhanced by Ca
2+
-induced Ca
2+
release. Such fluctua-
tions in the membrane potential of the Ca
2+
store
would continue as a burst of high-frequency voltage
fluctuations. In fact, an increase in intracellular [Ca
2+
]
coincides with an increase in DiOC
5
(3) fluorescence,
which is caused by the burst of high-frequency voltage
fluctuations [5].
It has been shown that voltage- and Ca
2+
-activated
K
+

channels [big K
+
channels (BK channels)] are
present in the membrane of the Ca
2+
store or the
ONM [4,7]. The store BK channels are activated by a
positive voltage change on the luminal side and by an
increase in the luminal [Ca
2+
] [4,7]. Because the clos-
ing of the store BK channels attenuates Ca
2+
release
[4], the Ca
2+
efflux will decrease when the luminal
Ca
2+
levels decrease to the point at which the store
BK channels close. The decrease in the luminal [Ca
2+
]
should also decrease the driving force for Ca
2+
efflux.
The closing of the store BK channels increases the time
constant for the store membrane to dampen the high-
frequency voltage fluctuation of the Ca
2+

store, which
will inhibit the synchronous burst of the voltage fluctu-
ations of the Ca
2+
store [5]. When the Ca
2+
store is
replenished with Ca
2+
ions by Ca
2+
pumps in the
store membrane, and the store BK channels are reacti-
vated, the voltage fluctuations of the Ca
2+
store will
resume.
Synchronous intracellular Ca
2+
increase in central nervous system
(CNS) development
Figure 2 illustrates the development of neural activities
relative to the cellular events that occur during the
course of CNS development. Neurons are born from
neuroepithelial cells after they have exited the cell
cycle. It has been shown that the Ca
2+
mobilization
(Ca
2+

release from Ca
2+
stores) and the synchronous
Ca
2+
oscillations are essential for neuroepithelial cell
proliferation, for ventricular cell proliferation, and for
cell cycle progression [8–17]. Thus, the synchronous
Ca
2+
oscillations continue during neurogenesis. Cell
death occurs naturally, leading to a reduction in the
M. Yamashita Capacitative electrical coupling of Ca
2+
release
FEBS Journal 277 (2010) 293–299 ª 2009 The Author Journal compilation ª 2009 FEBS 295
number of neurons by approximately one-half. The
surviving neurons begin to generate action potentials.
At this stage, the surviving neurons exhibit a charac-
teristic synchronous burst spiking, which leads to tran-
sient, synchronous increases in intracellular [Ca
2+
]
between the cells [18,19]. Although transmitters may
play a role in modulating the bursting activity, chemi-
cal transmission is unlikely to mediate the synchroniza-
tion of spikes between the cells [18] (discussed later). It
has been proposed that the synchronous increase in
intracellular [Ca
2+

] is essential for the fine-tuning of
synaptic connections [18–20]. Glial cells are born
following neurogenesis [21]. The glial cells provide elec-
trical insulation to neurons, thereby making it possible
for individual neurons to generate action potentials
asynchronously, depending on the synaptic inputs that
they receive. Thus, neural circuits are precisely formed,
and each neuron can respond to appropriate natural
stimuli.
Biological significance of Ca
2+
synchronicity
The above overview of the steps of CNS development
raises questions regarding the molecular events that
accompany the synchronous increase in intracellular
[Ca
2+
]. The following sections describe a new model
and provide possible explanations regarding the bio-
logical significance of the synchronous increases in
intracellular [Ca
2+
] between cells.
Cell cycle-dependent Ca
2+
mobilization and
cell–cell adhesion in the neuroepithelium
Neuroepithelial cells undergo interkinetic nuclear
migration along the apicobasal axis during cell cycle
progression [21,22]. Stimulation of G-protein-coupled

receptors causes the robust release of Ca
2+
from intra-
cellular Ca
2+
stores in S-phase cells in the basal layer,
whereas the ER and the nuclear envelope are broken
down and the Ca
2+
mobilization declines in M-phase
cells in the apical layer [12]. Spontaneous, synchronous
Ca
2+
oscillations occur between S-phase neuroepit-
helial cells and newborn RGCs [4,5].
The interkinetic cell shows a polarized bipolar struc-
ture, whereas the M-phase cell is round. Fujita and
Yasuda [23] have suggested that this morphological
difference is due to a change in cell–cell adhesion that
is mediated by cadherin–catenin complexes within each
cell and by cadherin–cadherin interactions between the
two cells. The interkinetic cells adhere to each other
via cadherin–catenin complexes, and these complexes
are anchored to F-actin (Fig. 3A). During M-phase,
the cadherin–catenin complex dissociates, thereby dis-
rupting cell–cell adhesion [23]. As a result, M-phase
cells are round (Fig. 3B). These morphological and
molecular changes point to a relationship between
cell–cell adhesion and the synchronous Ca
2+

oscilla-
tions, and suggest that cadherin–catenin complexes
connect interkinetic cells with each other. Synchronous
Ca
2+
oscillations occur in S-phase cells and newborn
RGCs. In contrast, in M-phase cells, the Ca
2+
mobili-
zation system, including the ER and the nuclear enve-
lope, disappears and cadherin–catenin complexes are
disassembled. It is proposed that cell–cell adhesion
may be regulated by the synchronous increases in
intracellular [Ca
2+
], as described below.
Synchronous increases in intracellular [Ca
2+
] and
disassembly of cadherin–catenin complexes
The cytoplasmic domain of cadherin interacts with
F-actin via b-catenin and a-catenin; b-catenin binds
to cadherin and a-catenin, which in turn interacts with
F-actin (Fig. 3A) [24]. Thus b-catenin plays a pivotal
role in the regulation of cell–cell adhesion. The interac-
tion of b-catenin with cadherin is regulated by tyrosine
phosphorylation of b-catenin [25,26], which leads to
disassembly of the cadherin–catenin complex. b-Cate-
nin is directly tyrosine-phosphorylated by the nonre-
ceptor protein tyrosine kinase proline-rich tyrosine

kinase 2 (Pyk2) [26,27], or is indirectly tyrosine-
phosphorylated by Src family kinase, which can be
activated by Pyk2 [28]. It is likely that tyrosine phos-
phorylation of b-catenin is triggered by Ca
2+
ions,
because Pyk2 is activated by an increase in intracellu-
lar [Ca
2+
] [29,30].
If Pyk2 is transiently activated by an increase in
intracellular [Ca
2+
] to phosphorylate b-catenin in two
Development of neural activities
Responses to
natural stimuli
Spiking in
individual neurons
Synchronous Ca oscillation
Proliferation Cell death
Gliogenesis
Synapse formation
Neurogenesis
Synchronous spikes
with Ca
2+
transients
Fig. 2. Changes in cellular activities during CNS development.
Capacitative electrical coupling of Ca

2+
release M. Yamashita
296 FEBS Journal 277 (2010) 293–299 ª 2009 The Author Journal compilation ª 2009 FEBS
adherent cells, the synchronous increase in [Ca
2+
]
between the cells could lead to a significant change in
the homophilic binding of cadherins. The coactivation
of Pyk2 ⁄ Src kinase between the cells would result in
the dissociation of cadherins (Fig. 3A). However, if
intracellular [Ca
2+
] were increased in only one of the
two adherent cells, the transient activation of Pyk2
would only occur in that cell. In this case, the b-cate-
nin would be rapidly dephosphorylated by a phospha-
tase in that cell without disrupting the homophilic
binding of cadherins (Fig. 3C).
If the synchronous increase in intracellular [Ca
2+
]
were responsible for the disruption of cell–cell adhe-
sion, it would seem paradoxical that the synchronous
Ca
2+
oscillations would occur in S-phase cells, but not
in M-phase cells. S-phase cells, however, may gradu-
ally disconnect themselves from the surrounding cells
before M-phase, at which point almost all cadherin–
catenin complexes are disassembled. After mitosis, the

cells are reattached by cadherins, and the ER and the
nuclear envelope are reorganized before S-phase.
Newborn RGCs are also free from surface adhesion as
they extend dendrites (Fig. 3B).
In summary, a new model is put forward in which
synchronous, transient increases in intracellular [Ca
2+
]
between cells can facilitate the disruption of cell–cell
adhesion to destabilize cell surface contact. A
reduction in the stability of cell–cell adhesion may be
an output of a coincidence detector of cellular activi-
ties. This decrease in cell-cell contact, in other words,
the increase in freedom of cell surface, may play an
essential role in the regulation of mitosis, dendrite
extension, and synaptic plasticity.
Capacitative (AC) electrical coupling in
cortical development
Synchronous Ca
2+
oscillations occur in the developing
cortex even before synapse formation [8,31,32]. Ca
2+
oscillations in the retinal ventricular zone are driven
by a muscarinic acetylcholine receptors (mAChRs),
which cause the release of Ca
2+
from intracellular
Ca
2+

stores [13,14,33]. The activation of mAChRs also
induces strongly synchronized electrical activities in the
subplate of the cortex of newborn mice [32]. The
mAChR-driven electrical activity is blocked by tetro-
dotoxin, suggesting that the activation of mAChRs
results in the generation of action potentials [32]. How-
ever, it remains unknown how the activation of
mAChRs induces the synchronous firing activity.
The capacitative (AC) coupling model may account
for the generation of synchronous bursts of spikes.
The AC currents caused by the voltage fluctuations of
the Ca
2+
store may pass the plasma membrane capaci-
tatively (Fig. 4A). This current may function as a noisy
stimulus current to evoke action potentials (Fig. 4B).
A
C
B
Fig. 3. Hypothetical role for synchronous
[Ca
2+
] increases in cell–cell adhesion. (A)
Simultaneous increases in intracellular
[Ca
2+
] in two adherent cells lead to disrup-
tion of cell–cell adhesion through disassem-
bly of cadherin–catenin complexes. (B)
Changes in cell shape and the plasma mem-

brane during mitosis and dendrite extension.
(C) An increase in intracellular [Ca
2+
] in only
one of two adherent cells does not disrupt
cell–cell adhesion.
M. Yamashita Capacitative electrical coupling of Ca
2+
release
FEBS Journal 277 (2010) 293–299 ª 2009 The Author Journal compilation ª 2009 FEBS 297
If the voltage fluctuations of the Ca
2+
store are syn-
chronous between the cells, synchronous bursts of
spikes could be generated. Such capacitative coupling
may be the underlying mechanism that mediates the
synchronization of spikes during the early stages of
neurodevelopment.
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0.1 s
A
B
Fig. 4. Capacitative (AC) coupling model for the generation of syn-
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M. Yamashita Capacitative electrical coupling of Ca
2+
release
FEBS Journal 277 (2010) 293–299 ª 2009 The Author Journal compilation ª 2009 FEBS 299