(Circulation. 1997;96:3761-3765.)
© 1997 American Heart Association, Inc.
Articles |
Role of the Diadic Cleft in Myocardial Contractile Control
From the Departments of Physiology and Medicine, Cardiovascular Research Laboratory, UCLA Center for Health Sciences, Los Angeles, Calif.
Correspondence to Dr G.A. Langer, Departments of Physiology and Medicine, Cardiovascular Research Laboratory, MRL-3645, UCLA Center for Health Sciences, 675 Circle Dr S, Los Angeles, CA 90095-1760. E-mail glenn{at}cvrl.ucla.edu
Key Words: calcium • contractility • muscles • diadic cleft • sarcoplasmic reticulum
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Introduction |
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The diadic cleft space is the region of the cell, in mammalian heart, between the JSR membrane and the inner leaflet of the T-tubular SL membrane. As results accumulate from various laboratories, the role of the cleft region in regulation of the calcium movements of the cell seems to be of considerable significance. Much remains to be learned about the region, but enough is currently known to warrant a brief perspective at this time.
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Contractile Control: Skeletal and Cardiac |
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In terms of calcium control of contraction, it is useful initially to compare this control in skeletal and cardiac muscle, because both demonstrate cleft structure: diadic in the heart, triadic in skeletal muscle. A simple experiment, which attracted little attention at the time, clearly showed that the process of excitation-contraction coupling is very different in skeletal and heart muscle. Armstrong et al1 showed that single fibers from frog semitendinosus muscle continued to contract for 20 minutes or longer when perfused with zero calcium plus EGTA ([Ca]0<10-8 mol/L). By contrast, removal of calcium from the perfusate bathing ventricular cells completely eliminates contraction within the period between two beats.2 Just before the Armstrong study, Endo et al3 demonstrated the process of CICR in skinned skeletal muscle fibers. Ironically, he later found4 that the process occurred only in heavily calcium-loaded or caffeine-treated skeletal SR and was not physiological for this tissue. Fabiato,5 6 however, in a series of seminal studies, later established that CICR played a physiologically crucial role in heart muscle. It then became obvious that excitation-contraction coupling was, indeed, very different in the two tissues and that events in the cleft space were dissimilar. In skeletal muscle, the L-type calcium channel, also known as the DHPR,7 acts as a voltage sensor that provides the signal for calcium release from the SR. By contrast, as is now well known, the L-type channel in cardiac muscle admits calcium to serve as a trigger for SR calcium release.6
The voltage dependence of the channel in skeletal muscle and its calcium dependence in cardiac muscle explain the very different responses of the two tissues to removal of extracellular calcium. They also explain the basis for contractile control in the two tissues. Skeletal muscle puts out more or less force by recruitment of more or fewer motor units via its nerve supply. If more force is required, the nerve-regulated voltage stimulus is applied to more cells and more force is not required from the individual cell. This is not the case for the heart, which, in terms of contraction, is classically "all or none." Normally, all cells contract or none contract. This means that force modulation must be at the level of the individual cell. It would seem that CICR is a mechanism ideally suited for fine tuning of force in that not only variation in the amount of trigger calcium but also its rate of entry affect the amount of calcium released by the SR6 and consequently the level of force developed by the cell. The CICR process takes place in the diadic cleft space of the cardiac cell.
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Pertinent Structure |
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Early electron microscopic studies8 9 noted couplings within the T tubules where the SL was in close apposition to the JSR. The narrow space or cleft between the SL and the JSR was bridged by structures originally called junctional processes and now called "feet." Fig 1
shows a cross section
of a T tubule with apposed JSR and the so-called feet spanning the
space between the two.10
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Characterization of the feet was facilitated by use of the drug
ryanodine, which has a fascinating history. The drug was first isolated
from a plant native to Trinidad and used as an insecticide. Its
negative inotropic effect on mammalian heart was reported 40 years
ago.11 12 It was noted, however, that frog or turtle
ventricles were not affected by the drug. Given the paucity of SR in
amphibian hearts, this, in retrospect, provided an early clue to its
site of action. Inui et al13 14 used tritiated ryanodine
and identified the feet as the ryanodine receptor sites. Negative-stain
electron microscopy revealed a foot as a fourfold-symmetric,
four-leaf-clover–like structure in the heart. Subsequent
studies15 using skeletal muscle ryanodine receptors showed
that a foot had the shape of a square prism with the dimensions
29x29x12 nm, with its tetrads forming a central channel connected to
channels opening at the sides of the foot. Present evidence
indicates that the feet penetrate the JSR membrane and serve as the
sites for calcium release through the central channels to the space
between the JSR and T-tubule SL membrane16 17 18 (see Fig 1
).
We have designated19 this space the diadic cleft, and it
seems to contain most of the elements important for control of calcium
movements within the mammalian cell. Hearts of species lower on the
evolutionary ladder (eg, amphibia) without significant SR have no cleft
structure and have less regulation of calcium-controlled contraction.
Also, in mammalian species, the calcium pump in the longitudinal SR
plays a significant role in the determination of cellular [Ca] and
particularly in the delivery of calcium to the JSR at the cleft
space.
Wibo et al20 found a concentration of L-type calcium
channels in the cleft of rat ventricle in close association with the
feet. They measured 84 calcium channels/µm2 cleft area
and 765 feet/µm2, a ratio of 9 feet to 1 calcium channel.
We have estimated the area of a single cleft or junction at
0.13 µm2.19 This would place 11
calcium channels and 100 feet within the cleft space. Confirmation of a
close association between feet (ryanodine receptors) and the calcium
channels comes from immunolabeling of the ryanodine receptors and DHPRs
(calcium channels) in the junctional domains (clefts) of cardiac
muscle.21 As stated, "the apposition of DHPRs and RyRs
indicated that most of the calcium current flows into the restricted
space where the feet are located." The "restricted space" can
be read as "cleft space." Thus, it seems that calcium from the
extracellular space via L-type channels enters the cleft and that
calcium release from the JSR also enters the cleft via the feet. The
cleft, then, is the region in which calcium release5 must
occur.
The main route for calcium flux out of the cell is via Na+/Ca2+ exchange.22 Localization of this exchange in the cell has been studied by use of fluorescently tagged monoclonal antibody to the exchangers.23 This shows a clear increase in concentration of the exchangers in the SL of the T tubules compared with the cell surface SL. The preferential localization to the T tubules is emphasized by following the migration of the Na+/Ca2+ exchangers during cell development.24 In rabbit ventricular cells at 5 days after birth (before T tubule development), immunofluorescence was intense but confined to the peripheral SL. After 11 days of age, the fluorescence followed the T tubules. The exchangers appeared in the tubules as soon as they were formed. The resolution of the confocal microscopy used is not sufficient to visualize the individual clefts. However, Page25 measured the junctional (cleft) area per total T-tubular area at 46% for rat ventricle. Therefore, it is reasonable to suppose a preferential localization of the exchangers to the clefts, because almost 50% of T-tubular area is apposed to a cleft. As will be discussed below, there is even more reason to place the exchangers at the cleft space from the point of view of optimizing their function. It should be noted, however, that a study by Kieval et al26 found a more uniform distribution of the exchangers, ie, both within the T tubules and on the peripheral SL. However, that study used polyclonal antibodies, and it is likely that they react at other SL sites to alter the fluorescent labeling pattern.
At least one more important structural consideration remains, and this
concerns the composition of the inner leaflet of the SL membrane at the
outer border of the cleft space (see Fig 2). It has been shown27 28
that SL contains two classes of calcium-binding sites, with those of
low affinity [Kd (Ca)=1.1 mmol/L]
accounting for >90% of the binding at saturating levels of [Ca].
These sites are inner leaflet phospholipids,
phosphatidylserine, phosphatidylinositol, and
phosphatidylethanolamine.27 These phospholipids have not
been specifically localized to the clefts, but it is reasonable to
suppose at least a homogeneous distribution over the SL,
including the clefts. These calcium-binding sites play a critical role
in the determination of calcium movements within the cleft space. Fig 2
summarizes the structure of the diadic cleft space. The figure serves
only to indicate the most important elements and is not to scale. There
is direct experimental support for the inclusion of all components
except for the sodium channels, which are shown to enter the space.
There is, however, extensive indirect support for sodium channel entry
into such a restricted region.29 30 31
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Calcium Movements in the Cleft |
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From the preceding review, it seems that the ventricular cell has concentrated Ca2+ and Na+ entry from the extracellular space, Ca2+ entry from its intracellular storage sites (JSR), and Ca2+ exit to the extracellular space, all within the diadic and subsarcolemmal clefts of the cell. Given the SL surface area of a diadic cleft and their T-tubular density,25 it is reasonable to assume a distribution of
1 cleft/2 half-sarcomeres.
Depending on species and cell size, an average cell would contain
10 000 diadic clefts. On the basis of a recently published model19 that includes all the elements of the cleft reviewed above and experimentally measured values for calcium and sodium channel influx, JSR calcium release, and Na+/Ca2+ exchange–mediated calcium efflux, we can outline a possible scenario for the calcium and sodium movements in the cleft space as they might occur over the course of a single cardiac cycle.
Calcium Channel Influx
A reasonable assumption for the current through a single calcium
channel is that it enters in the form of a 0.3-pA, 1-ms-duration
rectangular pulse.32 If the channel is located in the
center of an array of 9 feet within the cleft, all 9 feet will be
located within a radius of 50 nm from point of the current entry.
(Remember that Wibo et al20 found a ratio of 9 feet to 1
calcium channel.) At a distance of 50 nm, [Ca] in the cleft will
increase 10 times from its diastolic level of 0.1 to 1
µmol/L within 1.0 ms and increase another 10-fold to 10
µmol/L in the next 1 ms. According to Fabiato,6
an increase of [Ca] to 1 µmol/L in 1.0 ms will trigger
a release from the JSR via the feet sufficient to activate
50% maximum force; an increase to 4.0 µmol/L in 2 ms
will release enough calcium (assuming adequate JSR content) to produce
near-maximum force. Therefore, the diadic cleft, where calcium channels
are in close juxtaposition to the release channels, is ideally suited
as the locus for the process of CICR so elegantly described by Fabiato
more than 15 years ago. It is the place where calcium entry and JSR
content interact to set the level of calcium release and thereby the
level of force development for the cell.
Sodium Channel Influx
In the model, a sodium channel is assumed to deliver sodium at the
center of the cleft in a trapezoidal pulse reaching 2 pA within 0.5 ms,
remaining at this level for 0.5 ms and then decreasing linearly with
time to 0 pA within 0.5 ms.33 This current would produce
an increase in cleft [Na] of 10 mmol/L (from baseline
of 12 mmol/L) within 40 nm of the channel entry point
for the 0.5 ms that the current is at the 2 pA level. This rise of
[Na] in the cleft will cause the Na+/Ca2+
exchanger current to reverse or become outward (net movement of calcium
inward) at action potential plateau more positive than 0
mV.34 Therefore, as originally proposed by Leblanc and
Hume,29 there would be a transient net movement of calcium
into the cell via Na+/Ca2+ exchangers located
in the SL of the cleft. The movement would occur for, at most, a few
milliseconds when the membrane potential is at its peak positive value.
A number of studies35 36 indicate that the "reverse"
Na+/Ca2+ exchange could serve, under conditions
near physiological, to provide the calcium for
CICR. Conversely, some studies37 38 support the contention
that calcium release from the JSR is much more efficiently achieved by
calcium entering through the L-type channel. The cleft
model19 supports the latter. At best, according to the
model, [Ca] would increase to 0.5 µmol/L by "reverse
exchange" but would require 10 ms to do so. This would trigger
calcium release capable of producing no more than 20% maximal
force.6 Although Na+/Ca2+ exchange
in the cleft may or may not contribute to the process of CICR from JSR
under physiological conditions, its presence in the
cleft is of major importance in calcium efflux from the cell (see
below).
Calcium Release From JSR
After calcium entry into the cleft space through the channels, the
next step in the excitation-contraction sequence is calcium release
from the JSR via the feet. The details of this release (CICR) are not
yet established. Stern39 produced a strong theoretical
argument against a "common pool" model in which the
"trigger" calcium and released calcium are within the same
cytosolic pool. This model was not capable of producing a graded
release of calcium as is known to occur experimentally. Rather, two
types of "local control" were considered possible: (1) One L-type
calcium channel directly stimulates one immediately opposed SR
calcium- release channel; (2) one L-type channel triggers a
regenerative cluster of several SR release channels. Both were capable
of producing graded calcium release. There is, indeed, recent
experimental evidence40 for close opposition of L-type
channel and SR release channels. This study supported the existence of
microdomains within the cleft, which included a calcium channel and
ryanodine receptors (feet) but excluded
Na+/Ca2+ exchangers.
It has been difficult to understand why, once release starts from a release channel, it does not become regenerative and continue to put out more and more calcium. Györke and Fill41 have attributed a negative feedback mechanism for shutting down the channel to adaptation rather than inactivation as [Ca] elevates in the vicinity of the SR release channel. It is proposed that open probability peaks and then spontaneously decays (adapts) in the continued presence of elevated calcium. Results from whole cells are consistent with the "adaptation model."42 43 44
It should be noted that there is very recent, preliminary evidence that all SR channel release may not be calcium induced. Levi and Ferrier45 report a fraction of SR release dependent only on SL depolarization, a "voltage-activated calcium release." This, of course, is the release mechanism used by skeletal muscle (see above). It seems possible that cardiac muscle might use a combination of CICR and voltage-activated calcium release as well as reverse Na+/Ca2+ exchange.
Release of an amount of calcium sufficient to produce maximum force
(70 µmol/kg wet ventricle) will increase [Ca] in the
cleft spaces to >100 µmol/L at the end of a 20-ms
release.19 If such release were to occur into a restricted
space identical to that depicted in Fig 2, except for removal of the
inner leaflet anionic sites, [Ca] would rise to the same high levels
during release but return to the 100 nmol/L
diastolic level in <1 ms after release ceased. With the
anionic calcium-binding sites present, the model indicates that
150 ms is required for calcium to diffuse out of the space and for
[Ca] in the cleft to return to the 100 nmol/L level. Calcium
binding to the large quantity of inner leaflet sites (Fig 2) accounts
for the marked diffusional delay. The configuration of experimentally
measured individual release events, called calcium
"sparks,"46 measured by calcium-sensitive dyes is
consistent with the diffusional delay within the clefts as well
as, of course, with delays within the cytoplasm.
Therefore, the amount of calcium dispersed to the myofilaments depends on the JSR calcium content and the magnitude and rate of calcium entry through the L-type channels. All of the elements involved in this force-determining process are located at the diadic or subsarcolemmal clefts.
Na+/Ca2+ Exchange
We have discussed the role of cleft-based structures in calcium
flux through channels and release to the cytoplasm from the JSR. What
about removal of calcium from the cell? The major route for this
removal is Na+/Ca2+ exchange. It has been shown
that a reasonable value for intracellular calcium concentration,
[Ca]i, for half-maximal stimulation of the exchangers is
5 µmol/L (Kd
Ca).47 Depending on the amount of calcium released from
the JSR, [Ca]i in the bulk cytoplasm reaches peak levels
between 1 and 2 µmol/L for only 30 to 40 ms and then
falls to an average level of <1 µmol/L for the remainder
of the 150- to 200-ms [Ca] transient.48 If
Na+/Ca2+ exchange took place over the general
SL surface in response to bulk [Ca]i levels that are well
below the Kd of 5 µmol/L, it would
require 1 second for the exchangers to expel the amount of calcium
that had entered via the calcium channels.19 Efflux via
Na+/Ca2+ exchange has to match L-type channel
influx if steady-state intracellular calcium levels are to be
maintained. The SL Ca-ATPase plays little role in beat-to-beat calcium
efflux. Efflux via Na+/Ca2+ exchange matches
influx via calcium channels so as to maintain steady
state.49 50 Therefore, if the cell beat rate is >60/min,
a progressive increase of intracellular calcium would occur. This is
inconsistent with long-term cell survival.
As discussed earlier, there is considerable evidence to support
localization of a large fraction of the
Na+/Ca2+ exchangers of the cell in the SL at
the cleft spaces. Such placement will greatly enhance the activity of
the exchangers during the cardiac cycle. This is because [Ca] in the
clefts increases to >100 µmol/L during JSR release (20
ms), but more importantly, the model indicates an average value
>5 µmol/L for the next 100 ms. The maintenance
of high cleft [Ca] is due largely to the calcium-binding inner
leaflet sites, which delay diffusion of calcium from the cleft space
(Fig 2). These high [Ca] levels permit the exchangers in the clefts
to maintain steady-state intracellular calcium levels in the face of
beat rates of 
300/min. A recent study in which the inner leaflet
sites were neutralized showed that there is a markedly decreased
calcium efflux from the cells via Na+/Ca2+
exchange.51 This supports the importance of these
cleft-based sites in control of calcium efflux from the cell.
Therefore, current evidence strongly suggests that calcium influx, calcium storage, calcium release, and calcium efflux are based in cleft-associated structures. The proximity, within the cleft, of the structures involved in these functions seems to make sense in terms of feedback control of cardiac cellular calcium movements and contractility.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by PHS grant HL-28539-13 and the Laubisch and Castera Endowments.
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