Cardiovascular Research

Cardiovascular Research Advance Access originally published online on November 10, 2007
Cardiovascular Research 2008 77(2):315-324; doi:10.1093/cvr/cvm063

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Crosstalk between L-type Ca²⁺ channels and the sarcoplasmic reticulum: alterations during cardiac remodelling

Virginie Bito¹, Frank R. Heinzel^1,2, Liesbeth Biesmans¹, Gudrun Antoons³ and Karin R. Sipido^1,*

¹ Department of Cardiovascular Medicine, Division of Experimental Cardiology, University of Leuven, KUL Campus Gasthuisberg O/N 7th floor, Herestraat 49, B-3000 Leuven, Belgium
² Division of Cardiology, University Hospital Graz, Austria
³ Department of Medical Physiology, University Medical Center, Utrecht, the Netherlands

^* Corresponding author. Tel: +32 16 347153; fax: +32 16 345844. E-mail address: karin.sipido{at}med.kuleuven.be

Received 7 October 2007; revised 30 October 2007; accepted 1 November 2007

Time for primary review: 6 days

	Abstract

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
In the cardiac dyad, sarcolemmal L-type Ca²⁺ channels (LCCs) and sarcoplasmic reticulum (SR) Ca²⁺ release channels (RyR) are structurally in close proximity. This organization provides for an efficient functional coupling, tuning SR Ca²⁺ release for optimal contraction of the myocyte. Given that LCC are regulated by the prevailing [Ca²⁺], this structural organization is the setting for feedback mechanisms and crosstalk. A defective coupling of Ca²⁺ influx via LCC to activation of RyR has been implicated in reduced SR Ca²⁺ release in heart failure. Both functional changes in LCC properties and structural re-organization of LCC in T-tubules could be involved. LCC are regulated by cytosolic Ca²⁺, and crosstalk with SR Ca²⁺ handling occurs on a long-term basis, i.e. during steady-state changes in heart rate, on an intermediate-term basis, i.e. on a beat-to-beat basis during sudden rate changes, and on a very short- or immediate-term basis, i.e. during a single heartbeat. We review the properties and consequences of these different feedback mechanisms and the changes in heart failure and cardiac hypertrophy that have thus far been studied.

KEYWORDS Cardiac hypertrophy; Heart failure; Calcium channel; Sarcoplasmic reticulum; Excitation–contraction coupling; Arrhythmias

	1. The key role of the sarcoplasmic reticulum in cardiac myocyte contraction

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
During cardiac excitation–contraction coupling, the sarcoplasmic reticulum (SR) is the major source of Ca²⁺ influx into the cytosol. This large influx is essential to produce a rapid increase of the cytosolic [Ca²⁺] for activation of the myofilaments to be translated into a proper twitch contraction. In the absence of Ca²⁺ release from the SR, Ca²⁺ influx across the sarcolemma can produce cytosolic Ca²⁺ transients of large amplitude, but their slow rise precludes an efficient contraction. Ca²⁺ release from the SR occurs through the ryanodine receptor, RyR, and is triggered by a local increase in cytosolic Ca²⁺. The release flux and thus the rate of rise of cytosolic Ca²⁺ depend on the triggering and gating of the RyR and on the amount of Ca²⁺ available for release (see Ref. 1 for review).

The trigger Ca²⁺ can in theory be provided by several sarcolemmal pathways: L-type Ca²⁺ channels (LCCs), T-type Ca²⁺ channels, and reverse mode Na/Ca exchange, NCX. Quantitative differences exist in Ca²⁺ handling between different species, but for excitation–contraction coupling similar general principles apply.¹ In normal conditions, the LCC is the major pathway, due to its preferential location, close to the RyR, and its large single channel flux, resulting in an optimal trigger Ca²⁺ signal.^2–5 Both reverse mode and forward mode NCX can modulate the local trigger signal.^6,7 T-type Ca²⁺ channels can be re-expressed in pathological conditions, though their contribution to trigger SR Ca²⁺ release under those conditions was not yet specifically explored.^8,9

Ca²⁺ released from the SR in answer to the trigger Ca²⁺ influx is dependent on the properties of the RyR. Alterations in the gating properties of the RyR can occur due to changes in phosphorylation status of the RyR proper or to changes in the associated proteins such as FKBP12.6, triadin, and junctin (reviewed in¹⁰). The amount of Ca²⁺ available in the SR and thus the Ca²⁺ concentration inside the SR affect the driving force across the channel upon opening, but may in addition modulate RyR gating through luminal Ca²⁺ via its associated proteins.¹¹ Therefore the relation between triggered SR Ca²⁺ release and SR Ca²⁺ content is not linear and becomes highly non-linear at the high levels of SR Ca²⁺ content where spontaneous release occurs.^12,13

The major players in this excitation–contraction coupling process are structurally organized for optimal interaction. The LCCs and RyR form couplons at the interface between the sarcolemma and the junctional SR; they interact in a narrow space, the dyad.¹⁴ In ventricular cells, a network of T-tubules extending into the cell interior optimizes synchrony of excitation–contraction coupling throughout the myocyte.^15–17 In addition to LCC, the sarcolemma at these junctions also contains the Na/Ca exchanger (NCX), in proximity of other transporters involved in Na⁺ regulation.¹⁸ Given that both LCC and NCX proteins are regulated by the prevailing [Ca²⁺], this organization provides an optimal setting for feedback mechanisms.

In the present review, we will focus on the coupling of LCC to RyR and the feedback from SR Ca²⁺ release on LCC behaviour observed as the time course and amplitude of the L-type Ca²⁺ current. For the feedback we distinguish between (1) modulation with alterations in heart rate and (2) immediate modulation during a single cardiac cycle. In the first we distinguish between long-term alterations at different heart rates and a beat-to-beat, short term modulation with sudden alterations in heart rate. For each type of modulation we review the physiological data and available data on alterations in this crosstalk during heart failure or hypertrophy. The first chapter examines the changes in SR Ca²⁺ release proper during heart failure and hypertrophy.

	2. Sarcoplasmic reticulum Ca2+ release in heart failure

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
In the absence of alterations in myofilament response, reduced SR Ca²⁺ release is the single factor responsible for reduced myocyte contraction, as e.g. observed in end-stage heart failure. As outlined above, either a defect in the triggering and gating of RyR, or a reduced availability of SR Ca²⁺ must be involved. Recently there has been a shift in our understanding of underlying molecular mechanisms, emphasizing modulation rather than altered expression of Ca²⁺ transporters.¹⁹ The following is a brief summary of current data; Figure 1 summarizes the key elements that are elaborated in this and the next chapter.

View larger version (29K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Schematic of excitation–contraction coupling and changes with heart failure. During the action potential Ca2+ enters the cell through voltage-activated Ca2+ channels, LCC, with a small additional amount entering through the Na/Ca exchanger, NCX, depending on the [Na+]i. This Ca2+ acts as trigger to activate the Ca2+ channel in the sarcoplasmic reticulum, the ryanodine receptor, RyR, and more Ca2+ is released from the sarcoplasmic reticulum, the major source for Ca2+ to activate the myofilaments. Ca2+ is removed from the cytosol by re-uptake into the sarcoplasmic reticulum by the ATP-driven Ca2+ pump, SERCA, which is modulated by phospholamban, PLN, and by efflux through NCX. Some Ca2+ is removed by an ATP-driven Ca2+ pump in the sarcolemma, PMCA (data not shown). With heart failure there is a decrease in Ca2+ release from the sarcoplasmic reticulum. This is the result of changes in the triggering process (defective coupling) and of a decrease in available Ca2+. For the first, alterations in LCC and coupling can occur through different mechanisms. For the reduced Ca2+ content of the SR, several individual transporters are involved: enhanced removal through NCX, reduced uptake by SERCA and leak through RyR. Their function is regulated through altered expression but also through phosphorylation.

 
Studies of end-stage human heart failure have shown that SR Ca²⁺ content was reduced at physiologically relevant stimulation frequencies.^20,21 Molecular studies at first focused on the expression of the SR CaATPase, SERCA, with several reports, but not all, indicating a reduction in SERCA (reviewed in²²). More recent studies identified a key role for the regulatory protein phospholamban (PLB). Reduced phosphorylation of PLB, and hence enhanced inhibition of SERCA, was reported in tissues from human end-stage heart failure and in an animal model.^23,24 Modulating phosphorylation through the inhibitor I-1 of phosphatase PP1 could increase SERCA uptake.²⁵ In contrast in the MLP^–/– mouse with heart failure due to knockout of muscle LIM protein, a component of the cytoskeleton, we observed a high degree of basal PLB phosphorylation, yet with a limited possibility of the SR to enhance its Ca²⁺ uptake during high frequency stimulation.²⁶ In this case, the enhanced PLB phosphorylation could represent a mechanism to offset increased RyR phosphorylation and Ca²⁺ leak. In atrial fibrillation as well, a higher degree of PLB phosphorylation was reported and could interact with increased RyR leak.²⁷ Hyperphosphorylation of RyRs could lead to a reduced SR Ca²⁺ content through diastolic ‘leak’ because of enhanced Ca²⁺ sensitivity of the RyR.²⁸ NCX can contribute to enhanced loss of Ca²⁺ across the sarcolemma in the presence of a reduced SERCA activity or increased SR Ca²⁺ leak, but eventually the net result of increased NCX activity is dependent on the prevailing Ca²⁺ as well as Na⁺ concentrations.^29–31

In contrast to the reduced SR Ca²⁺ release in myocytes from end-stage heart failure and a number of experimental models of heart failure, there are reports that in compensated hypertrophy with preserved myocyte function, SR Ca²⁺ release is not reduced, and sometimes even enhanced. Typical examples include pressure overload in its early stages³² and some models of volume overload such as the dog with chronic AV block, cAVB.³³ In the case of the cAVB dog, LCCs were unchanged but an increased SR content was seen, ascribed to an increase in intracellular Na⁺.³⁴ In the myocytes from the rats with hypertension and compensated hypertrophy, neither LCC nor SR Ca²⁺ content were changed and the larger SR Ca²⁺ release was proposed to result from a more efficient coupling between LCC and RyR.³²

	3. L-type Ca2+ channels and coupling to RyR in heart failure

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
A reduction of ‘trigger’ Ca²⁺ influx via LCC was one of the first potential mechanisms for reduced SR Ca²⁺ release in heart failure that was investigated. Early studies of myocytes from human heart failure examined the amplitude and density of the whole-cell L-type Ca²⁺ current as a measure for the number of functional LCC.^35,36 Overall these studies failed to observe differences, though there were data from binding studies that suggested a decrease in channel number (reviewed in³⁷). Subsequent studies of single channel activity however indicated that the single channel activity was increased,³⁸ which, together with an unchanged whole-cell current, implied that the number of channels was reduced. Chen et al.³⁹ confirmed the unaltered whole-cell current, but also demonstrated that the response to cAMP in heart failure myocytes was reduced. Taken together these data could be explained by a reduction of the number of channels, which have a higher activity because of a higher adrenergic stimulation. Changes in phosphorylation are likely to play a major role for several Ca²⁺ handling proteins, such as the RyR and PLB.^28,40,41 The kinases and phosphatases involved may not be restricted to the adrenergic system. There is indeed emerging evidence for a major role for the CaMKII system in heart failure,⁴² which is well-known to modulate the LCC activity (see sub section 4).

The phosphorylation hypothesis of Ca²⁺ transporters as key event in heart failure does however not address the loss of LCC units that is inferred from data obtained in human heart failure. When studying myocytes from the infarct border zone, Litwin et al.⁴³ noticed a reduction in the whole-cell Ca²⁺ current density. The subcellular release events measured during confocal line scanning became less synchronous and the time course of the [Ca²⁺]_i transient was slowed. An analysis of spark properties in normal myocytes could identify the number of LCC in a couplon, the functional unit of LCC and RyR responsible for sparks.^44,45 These results support the concept that dyssynchrony can be due to a reduction in couplon size, i.e. a lower number of LCC in a couplon.

Another view on how SR Ca²⁺ release could be decreased in heart failure was offered by Gomez et al.⁴⁶ who introduced the concept of ‘defective excitation-contraction coupling’. In myocytes from the spontaneously hypertensive rat (SHR) with heart failure these authors observed a reduction in triggered Ca²⁺ release from the SR despite unaltered whole-cell Ca²⁺ current and SR Ca²⁺ content (Figure 2). Similar observations were later made in myocytes from rats with heart failure after myocardial infarction.⁴⁷

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Defective coupling in heart failure. L-type Ca2+ current and Ca2+ transient in a myocyte from a control WKY rat and from an SHR with heart failure, data matched from similar amplitude of LCC. Although the SR Ca2+ content in myocytes from both groups was comparable (data not shown), the amplitude of the Ca2+ transient, reflecting triggered SR Ca2+ release, is smaller in heart failure. A study on isolated RyR in bilayers showed a normal response of RyR to Ca2+, leading to the conclusion that the coupling between LCC and RyR was defective. Figure adapted from46, reprinted with permission from AAAS.

 
The concept of defective coupling is somewhat tricky and relies on a measurement of ‘gain’, defined as the relation between Ca²⁺ influx and Ca²⁺ release, usually approximated as the amplitude of the cytosolic Ca²⁺ transient. A proper comparison of ‘gain’ between conditions requires that there are no differences in SR Ca²⁺ content that would independently affect the amplitude of Ca²⁺ release. In many models of heart failure or hypertrophy, SR content is different from control conditions and evaluation of gain or coupling is difficult. Despite this difficulty, several models and studies have addressed potential mechanisms for defective coupling.

In the original paper it was speculated that among other mechanisms a structural alteration in the relation between LCC and RyR could entail the observed defective coupling.⁴⁶ Given the specific organization of LCC and RyR in the dyad, this was a plausible hypothesis. A first paper on structural changes in heart failure by He et al.⁴⁸ described a loss of T-tubules in myocytes from dogs with tachycardia-induced heart failure. The same group subsequently showed that in the remaining junctional complexes, the relation between sarcolemmal and SR proteins was preserved.⁴⁹ The consequences of a loss of T-tubules for excitation–contraction coupling and sarcolemmal Ca²⁺ flux were studied during acute detubulation and following loss of T-tubules in cell culture.^50,51 Both approaches similarly demonstrate the loss of synchrony of Ca²⁺ release with appearance of temporal and spatial inhomogeneities in Ca²⁺ release from the SR. A profound loss of T-tubules in these studies was accompanied by a reduction in the whole-cell Ca²⁺ current and average density of LCC. This can be seen as consistent with a preferential location of LCC in T-tubules. In this respect, however, the data differ from the early observations in the rat where Ca²⁺ current was unaltered.⁴⁶ Recently, Song et al.⁵² re-examined this same rat model of heart failure, looking at ultrastructure and local release events. They examined the relation between RyR and LCC and found that several RyRs were no longer closely associated with T-tubules. The presence of these ‘orphaned’ RyRs resulted in a loss of synchrony of Ca²⁺ release events. This is consistent with computations that small alterations can have profound effects on coupling in the dyad.⁵³ The same study also described qualitative changes in the 3D architecture of T-tubules in myocytes isolated from patients with end-stage heart failure, resulting in a reduction of the typical radial pattern of T-tubules, in favour of more longitudinally arranged T-tubules. In mice after myocardial infarction as well, discreet changes in the organization rather than a frank loss seem to occur⁵⁴ (Figure 3A).

View larger version (47K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3 Alterations in T-tubules after myocardial infarction. (A) Examples of a confocal image through the cell interior after staining sarcolemma and T-tubules with di-8-ANEPPS from mouse control hearts and from the myocardium left after myocardial infarction, showing a loss in regularity of the longitudinal T-tubule pattern. Figure modified after54, used with permission (Wiley-Blackwell Publishing Ltd.). (B) Ventricular myocytes isolated from the area adjacent to a myocardial infarction and from the same region in a matched control pig heart (CTRL) with average data for signal density of T-tubules. Figure based on data described in55.

 
We examined myocytes isolated from regions adjacent to a myocardial infarction and subtended by a severely stenosed coronary artery in pigs.⁵⁵ In this animal, at baseline, T-tubules are sparser than in the rodent hearts.¹⁶ Yet with remodelling in chronic ischaemia, there is a further reduction in the volume density of the T-tubule system without changes in the RyR organization (Figure 3B). The SR Ca²⁺ release is less homogeneous and the [Ca²⁺]_i transient overall slower, despite a preserved SR Ca²⁺ content. Whole-cell Ca²⁺ current is unchanged, more in line with the data observed in the rat model of heart failure, probably indicating that LCC are less confined to T-tubules in this animal than in rodents, in line with earlier findings.⁵¹

In summary, both functional changes in LCC activity and structural organization of the dyad with lower numbers of LCC coupling to RyRs can reduce excitation–contraction coupling efficiency during cardiac remodelling. This can occur with, but also without, apparent major changes in the whole-cell Ca²⁺ current.

	4. Modulation of LCC during changes in heart rate and crosstalk with sarcoplasmic reticulum Ca2+ handling

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
A typical observation in myocardium of patients with end-stage heart failure is the absence of a positive inotropic effect with increasing stimulation frequency with often a frank negative response instead.^21,56 In human failing myocardium there is a lack of increase in the SR Ca²⁺ content, related to a reduced SERCA function²¹ and possibly the presence of high intracellular [Na].^57,58 Few studies have examined a potential role for a frequency-dependent decrease in trigger Ca²⁺ influx.

Several years ago we showed that in myocytes from patients in end-stage heart failure the amplitude of the peak Ca²⁺ current decreased at higher stimulation frequencies.⁵⁹ This was clearly related to the prevailing elevated diastolic Ca²⁺ at higher frequencies (Figure 4). Indeed, because of the slow Ca²⁺ removal there was incomplete recovery of LCC and accumulation of inactivation at high frequencies. Therefore it is plausible that this mechanism will be particularly prominent in the failing heart with reduced Ca²⁺ removal capacity. We had, and have, however no access to non-failing human heart tissue and could not directly test this hypothesis. Li et al.⁶⁰ confirmed our data in heart failure, but also could not compare to non-failing hearts. Recently, the relation between rate-dependent diastolic Ca²⁺ accumulation and reduction in LCC was established in normal rabbit cardiac myocytes, showing an inverse relation between diastolic [Ca²⁺] and rate of recovery from inactivation (Figure 4B).⁶¹ There are at present to our knowledge no other studies that have investigated the steady state properties of peak Ca²⁺ influx at different and relevant frequencies in heart failure. We examined frequency dependence of Ca²⁺ release and Ca²⁺ current in the MLP^–/– mouse with heart failure.²⁶ In these animals we saw a frequency-dependent loss of peak Ca²⁺ influx but it was not different from control animals. This is not inconsistent with our hypothesis since in these mice SR Ca²⁺ uptake is preserved, but further studies in models with reduced SR uptake capacity are needed to establish the contribution of this rate-dependent modulation of LCC to the heart failure phenotype.

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 4 Inhibition of peak LCC at high frequency—Ca2+ dependence. (A) Ca2+ currents and Ca2+ transients were recorded at steady state at the indicated frequencies. The single myocytes were isolated from human LV tissue obtained at the time of heart transplantation in patients with ischaemic and dilated cardiomyopathy. The dotted line in the current traces at 2 Hz shows the current at the start of stimulation. The reduction in current at 2 Hz was fully reversible when stimulation was stopped and resumed at low frequency. Figure modified after59. (B) Time constant of recovery from inactivation of LCC at four different diastolic [Ca2+]i: 0, 100, 300, and 600 nM; data obtained at –70 mV (*, P < 0.05). Figure modified after61.

 
In addition to modulation of LCC at different steady state heart rates, short-term modulation during sudden changes in rate occurs. Facilitation (reviewed in⁶²) is an increase of Ca²⁺ influx via LCC during the first pulses at an increased rate of stimulation, starting from very low rates or from rest. The increase in the influx is predominantly a slowing of the time course of inactivation of the current, rather than an increase in peak current.⁶³ Delgado et al.⁶³ showed that facilitation reflects feedback from SR Ca²⁺ release and predominantly occurs because SR Ca²⁺ release is reduced during the increase in rate; after a relatively large SR Ca²⁺ release with the rested state beat or the low frequency, the following beats have a lesser amount of SR Ca²⁺ release, with a smaller degree of Ca²⁺-dependent inhibition of LCC (Figure 5).

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 5 Facilitation of LCC in rat ventricular myocytes. The top panel illustrates the facilitation seen as a slowing of the rate of decline of LCC and a modest increase in peak current between beat 1 and 7 after stepping from rest to 0.1 Hz. In parallel the Ca2+ transient is strongly reduced. In the presence of thapsigargin, which suppresses SR Ca2+ release there is no more variation in the Ca2+ transient with stimulation and likewise facilitation is absent. Figure modified after63, copyright Elsevier (ISHR).

 
Anderson and coworkers⁶⁴ have shown that facilitation depends on activation of CaMKII. The Ca²⁺ signal for the CaM signalling is probably provided by SR Ca²⁺ release as it is suppressed in the presence of ryanodine, but it is often observed in the presence of moderate cytosolic Ca²⁺ buffering with EGTA, suggesting local control.⁶⁵ The translation of Ca²⁺ signals via direct binding to LCC of Ca–CaM and via CaMKII appears to be complex and may even be modulated by voltage-dependent gating effects on LCC.⁶⁶ A site for direct phosphorylation by CaMKII was recently identified on the beta subunit of the LCC.⁶⁷ On the other hand, an SR-targeted inhibitor of CaMKII also suppressed facilitation, suggesting that the SR is a major site involved in facilitation.⁶⁸ During stimulation at high rates after rest, facilitation is a transient phenomenon that can be followed by a decrease of the current amplitude as described earlier.⁶⁹ Facilitation is thus a very dynamic process particularly relevant during sudden rate changes and following pauses. The larger Ca²⁺ influx prolongs and increases the plateau of the action potential in rat ventricular myocytes.⁷⁰ The presence of CaMKII has been linked to a higher incidence of early afterdepolarizations and triggered arrhythmias.⁷¹ In a recent study, beat-to-beat variability in [Ca²⁺]_i was related to LCC facilitation and CaMKII activity, further emphasizing the link between SR Ca²⁺ release, CaMKII, and facilitation.⁶⁹

Richard and coworkers⁷² also investigated the link between facilitation and RyR activity. Enhancing RyR opening through inhibition of FKBP12.6 increased facilitation and had a permissive effect on development of EADs. However, peak Ca²⁺ current was decreased illustrating the potential of both inhibition and facilitation by Ca²⁺ release.

Is facilitation altered in heart failure? The link to CaMKII and to SR Ca²⁺ release suggests that it may be, but at present published data are few. In human atrial cells from patients with heart failure, facilitation was decreased⁷³ but more studies are needed.

In summary, SR Ca²⁺ release can induce a beat-to-beat variation in the behaviour of the LCC with facilitation mediated through CaMKII and contributing to arrhythmogenesis. In long-term changes with frequency, increases in diastolic Ca²⁺ with reduced Ca²⁺ removal as in heart failure may reduce the availability of Ca²⁺ channels and trigger Ca²⁺, contributing to the negative force–frequency response of heart failure.

	5. Sarcoplasmic reticulum Ca2+ release and modulation of Ca2+ influx during a single beat

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
Rate-dependent inhibition and facilitation describe beat-to-beat variations in Ca²⁺ influx. During a single beat there is however also an immediate feedback of SR Ca²⁺ release on the LCC. As reviewed in,⁶² several early studies described the Ca²⁺-induced inactivation of LCC. This was at first focused on Ca²⁺ influx as source for modulation of the channel. Structure-function analysis through mutagenesis in heterologous expression systems also relied almost exclusively on this source of Ca²⁺ to identify the site for Ca–CaM binding in the N-terminal residues, responsible for rapid Ca²⁺-dependent inhibition.⁷⁴ In cardiac cells, SR Ca²⁺ release is however the major component determining rapid inactivation of Ca²⁺ channels immediately following depolarization. This has been demonstrated using inhibitors of SR Ca²⁺ release and varying the amplitude of SR Ca²⁺ release.^2,3,75 An analysis of the decay of LCC during Ca²⁺ release from the SR typically shows a bi-exponential time course with a component with very short time constant dominating the early decay and related to Ca²⁺ release. Several studies have reported a more pronounced inactivation of LCC than predicted from the free [Ca²⁺]_i measured with fluorescent indicators, occurring even in the presence of Ca²⁺ buffers such as EGTA.^2,3,75 These data underscore the privileged signalling and feedback between LCC and RyR.

In heart failure, the reduced amplitude and slower time course of Ca²⁺ release is expected to reduce the extent of Ca²⁺-dependent inactivation of the LCC. One problem with the analysis of the time course of the Ca²⁺ current in physiological conditions is that Ca²⁺ release also activates inward Na/Ca exchange current, which superimposes. This may confound measurement of changes in time course in different conditions and can explain why a modelling study predicted important changes in Ca²⁺ current decay⁷⁶ but experimental measurements of the time constant of the whole-cell current decay were not different.⁷⁷

Measurements of Ca²⁺ current in Na⁺-free conditions allow for a precise evaluation of the time course of SR release-dependent modulation, within the limitations of inducing Ca²⁺ overload caused by the inhibition of Na/Ca exchange. Such recordings reveal not only the inhibition of the LCC but also the recovery following re-uptake of Ca²⁺ into the SR.⁷⁵ We have been particularly interested in the phenomenon of recovery as it could contribute to the generation of EADs by enhancing the availability of LCC. The dog with chronic atrioventricular block, cAVB, for 6 weeks is a model for compensated hypertrophy as cardiac function is preserved and even enhanced.⁷⁸ At the myocyte level, SR Ca²⁺ content at low frequencies of stimulation is larger than in control.³³ The cAVB dog is more susceptible to arrhythmias and one provoking factor is adrenergic stimulation. Given the unusual SR Ca²⁺ handling, we were interested to see whether the feedback of Ca²⁺ release on LCC was different in cAVB and could help to explain the higher incidence of EADs under adrenergic stimulation.⁷⁹ We confirmed previous data that the peak inward LCC was not different between cAVB and control, but the early component of inactivation, related to SR Ca²⁺ release, was faster. We recorded Ca²⁺ currents in the absence of Na⁺ first to visualize the time course of inhibition and recovery during Ca²⁺ release. In Figure 6A, the top current trace recorded during a step to –35 mV (highlighted in the rectangle) has inhibition and recovery; superimposed are current traces recorded when stepping to 0 mV at various time intervals during the step to –35 mV. Such steps maximally activate LCC and the peak current of this step shows availability of LCC, and thus reflects the degree of inactivation/inhibition. Figure 6B illustrates that the time course of the current at –35 mV (green dots) and the peak currents at 0 mV (red dots) show a very high degree of correlation in regression analysis. This implies we can use the data from test steps to 0 mV to examine the degree of inhibition and recovery. This was done under conditions of Ca²⁺ buffering with EGTA as in Figure 6 and without Ca²⁺ buffering, shown in Figure 7. In both conditions the degree of inhibition and recovery tended to be higher in myocytes from cAVB. We postulate that the high degree of modulation contributes to the availability of LCC for EADs. The cAVB dog stands out from heart failure models in this respect since at this stage it has a preserved SR Ca²⁺ uptake and release. It would be interesting to examine the feedback of SR Ca²⁺ handling on LCC availability in conditions of heart failure and reduced SR uptake, but such data are currently not yet available.

View larger version (25K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 6 Modulation of Ca2+ current by SR Ca2+ release during a single beat. (A) The current during a step to –35 mV (highlighted in the rectangle) has a transient decrease and recovery. This is reflected in the availability of L-type Ca2+ channels as tested by the peak inward current during depolarizing steps to 0 mV at different times. A spike of fluorescence can also be recorded. The solutions are Na+ and K+-free, the pipette solution contains 10 mM EGTA and 200 µmol/L fluo-3; recorded in the presence of isoproterenol 300 nmol/L; dog LV myocyte. (B) Comparison of the time course of the current at –35 mV and the peak inward current at 0 mV: top panel, values after normalization to peak inward current; bottom panel correlation analysis and regression (r = 0.96, P < 0.001, slope 1.18). Figure modified after79, used with permission (Wiley-Blackwell Publishing Ltd.).

 

View larger version (28K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 7 Dynamic modulation is larger in myocytes from the dog with cAVB. (A) Extent and time course of LCC inhibition and recovery in the absence of EGTA and with external Na+ present can still be read from the test steps to 0 mV though the current at –35 mV is now a mixture of LCC and NCX. The time course of modulation of LCC is markedly faster than the time course of the global [Ca2+]i transient. (B) The extent of inhibition and modulation is larger in cells from cAVB. Data from79, used with permission (Wiley-Blackwell Publishing Ltd.).

 
In summary, during a single beat SR Ca²⁺ release and uptake will determine the time course and availability of LCC. This modulates the time course of the action potential and can contribute to arrhythmogenesis in heart failure and cardiac hypertrophy.

	6. Summary and perspectives

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
The structural organization of LCC and RyR in close proximity in the dyad provides for an efficient functional coupling, tuning SR Ca²⁺ release for optimal contractile function of the ventricular myocyte. With cardiac remodelling this coupling process may be disturbed by functional changes in LCC and RyR, as well as by changes in the structural organization.

The feedback of SR Ca²⁺ release on LCC occurs on an immediate basis during a single beat with SR release-dependent inhibition of Ca²⁺ influx followed by recovery. With sudden increases in heart rate following a pause or long inter-beat interval, a temporary facilitation of LCC can be seen. In contrast, with prolonged stimulation at high rates, a reduction in peak Ca²⁺ influx can occur. Cardiac remodelling alters this crosstalk between LCC and RyR because SR Ca²⁺ release is different and possibly because of changes in the spatial organization of LCC and RyR.

Novel and recent strategies to treat heart failure targeting Ca²⁺ handling include increasing SERCA activity by increasing protein level or PLB phosphorylation using gene therapy,⁸⁰ and possibly by altering RyR gating.⁸¹ All these interventions are expected to improve SR Ca²⁺ release but also to affect the time course and amplitude of LCC, and thus of the action potential. This will have to be taken into account. CaMKII as a therapeutic target⁸² is expected to directly affect crosstalk, as well as indirectly through its effect on SR Ca²⁺ release.

Lastly, data on structural remodelling of the LCC-RyR spatial organization are just emerging. Reversing such changes may be a desirable goal but will require much more insight in the mechanisms guiding T-tubule and SR structures. Perhaps we can learn from developmental biology as this specific organization seems to be part of the last stages of postnatal development.

Conflict of interest: none declared.

	Funding

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 
FWO, Fund for Scientific Research, Flanders (G. 0166.03 N to K.R.S.); the Belgian Science Program (IAP6/31 to K.R.S.); EU FP6 (LSHM-CT-2005-018833, EUGeneHeart to K.R.S.); NWO, Netherlands Organization for Scientific Research (916.56.145 to G.A.).

	References

Top Abstract 1. The key role... 2. Sarcoplasmic reticulum Ca2+... 3. L-type Ca2+ channels... 4. Modulation of LCC... 5. Sarcoplasmic reticulum Ca2+... 6. Summary and perspectives Funding References

 

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