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(Circulation Research. 2000;87:8.)
© 2000 American Heart Association, Inc.

MiniReview

Cardiac Intracellular Calcium Release Channels

Role in Heart Failure

Andrew R. Marks

From the Center for Molecular Cardiology, Departments of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to Andrew R. Marks, MD, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians & Surgeons, Room 9-401, 630 W 168th St, New York, NY 10032. E-mail arm42{at}columbia.edu

Key Words: calcium channels • excitation-contraction coupling • heart failure

	Introduction

Top Introduction References

 
This MiniReview is part of a thematic series on Calcium Cycling in Cardiovascular Cells, which includes the following articles: Ca²⁺ Release Mechanisms, Ca²⁺ Sparks, and Local Control of Excitation-Contraction Coupling in Normal Heart Muscle Interaction Between Ca²⁺ and H⁺ and Functional Consequences in Vascular Smooth Muscle

Cardiac Intracellular Calcium Release Channels: Role in Heart Failure

Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction

C. William Balke, Guest Editor

Calcium (Ca²⁺) ions are second messengers in numerous signaling pathways in all cell types.¹ In the heart, Ca²⁺ regulates muscle contraction, electrical signals that determine the cardiac rhythm, and probably plays a role in controlling cell growth.² In the last decade, elucidation of the molecular structure of the intracellular Ca²⁺ release channels on the sarcoplasmic reticulum (SR) and endoplasmic reticulum has led to an understanding of how these molecules regulate Ca²⁺ homeostasis in the heart. Consequently, the role of these channels (ryanodine receptors [RyRs] and inositol 1,4,5-trisphosphate receptors [IP₃Rs]) in cardiac pathophysiology is beginning to be understood.

Intracellular Ca²⁺ release channels form a unique class of ion channels distinguished on the basis of structure, size, and function (Figure 1). RyRs and IP₃Rs have large cytoplasmic domains that are involved in the regulation of the channel pore located in the carboxy terminal 10% of the channel sequence. The channels are tetrameric structures composed of 4 RyR or IP₃R subunits. There are 3 forms of RyRs and 3 forms of IP₃Rs (Table). The RyR subunits are each 600 000 daltons and the IP₃R subunits are each 300 000 daltons, yielding molecular masses for the single channels of 2.4 million and 1.2 million daltons, respectively. These channels are 10 times larger than the voltage-gated Ca²⁺ and Na⁺ channels, with Ca²⁺ conductances on the order of 100 pS (compared with 10 pS for the voltage-gated Ca²⁺ channels).

View larger version (38K): [in this window] [in a new window]   Figure 1. A, RyR2 is depicted as a 4-fold symmetrical macromolecular signaling complex on the SR membrane. The components of the signaling complex are indicated in the legend.10 The 4 putative barrels or pores through the SR membrane are based on data showing discrete subconductance states that are multiples of one fourth of the total conductance when FKBP12 and FKBP12.6 are removed from RyR1 or RyR2.20 Each subunit of the channel may form a pore through the SR membrane. FKBP12 and FKBP12.6 are required to enable the 4 subunit pores to gate as one unit. B, Approximate location of components of the RyR2 macromolecular signaling complex in the signaling complex domain of the cytosolic portion of the channel.10 S* indicates serine 2809, which is the site of PKA phosphorylation.10 The location of the mAKAP binding site (dashed line) has not yet been reported. RII indicates the regulatory subunit of PKA.

View this table: [in this window] [in a new window]   Table 1. Intracellular Calcium Release Channels

RyR2 is the major Ca²⁺ release channel required for excitation-contraction (EC) coupling in the heart. RyR2 is a Ca²⁺-gated channel.³ The major forms in the heart, RyR2 and IP₃R2,⁴ both exhibit bell-shaped⁵ dependencies on cytosolic Ca²⁺ such that they are activated at low (nmol/L to µmol/L ranges) [Ca²⁺] and inhibited at mmol/L ranges of [Ca²⁺]. Luminal SR Ca²⁺ also plays a critical role in regulating channel activity; as the Ca²⁺ level in the intracellular store falls, the open probability of the channel is decreased.^{6 7} Ca²⁺ influx via the voltage-gated Ca²⁺ channel (L-type channel or dihydropyridine receptor [DHPR]) activates RyR2.^{8 9} RyR2 opening increases cytosolic Ca²⁺ from 100 nmol/L to 1 µmol/L and activates Ca²⁺-sensitive contractile proteins (eg, troponin C) that trigger muscle contraction. Cardiac muscle relaxation requires Ca²⁺ removal from the cytosol primarily via the Ca²⁺ pump in the SR (SERCA2a). A defect in Ca²⁺ release could impair contractility or contribute to diastolic depolarizations (afterdepolarizations)¹⁰ that can trigger ventricular arrhythmias,¹¹ possibly by activating an inward depolarizing current via the sodium-calcium exchanger; a defect in Ca²⁺ removal could also impair relaxation.

RyR2 levels are downregulated in failing hearts, whereas IP₃R2 is increased.¹² However, it is more likely that altered Ca²⁺ signaling in cardiomyocytes results from modulation of channel function rather than regulation of channel levels. Recently, a defect in EC coupling gain has been reported in animal models of cardiomyopathy.¹³ Diminished EC coupling could occur if RyR2 channels had altered sensitivity to activation or inactivation or if the SR was relatively depleted of Ca²⁺. Another possible cause of a loss of EC coupling gain would be inhibition of coupled gating among the Ca²⁺ release channels.¹⁴ Coupled gating, which requires FKBP12, ensures that all the RyR channels on an SR membrane open and close simultaneously.¹⁴ Coupled gating may provide a mechanism whereby the Ca²⁺ signal for EC coupling can be efficiently regulated,^{14 15} particularly with regard to its termination, which is critically important to permit relaxation (and refilling of the heart chambers) and prevent diastolic depolarizations that can trigger ventricular arrhythmias (Figure 2).

View larger version (35K): [in this window] [in a new window]   Figure 2. Physiological and pathophysiological regulation of Ca2+ homeostasis by stimulation of the sympathetic nervous system resulting in phosphorylation of Ca2+-handling molecules in the heart. In healthy heart (left), RyR2 is relatively nonphosphorylated by PKA. (Identity of the components of the RyR2 macromolecular signaling complex is described in Figure 1.) Physiological stimulation (middle) in response to a threat (eg, the fight-or-flight response) results in increased circulating catecholamine levels, and PKA substrates are phosphorylated. PKA phosphorylation increases EC coupling gain (because of a slight increase in the Ca2+ sensitivity for activation of RyR2, such that for a given Ca2+ trigger entering via the DHPR, more SR Ca2+ is released via RyR2). PKA phosphorylation of RyR2 at 1 or 2 of the 4 sites on the channel causes dissociation of 1 or 2 of the 4 FKBP12.6s. Concomitant phosphorylation of phospholamban results in increased SERCA activity, thereby increasing Ca2+ reuptake into the SR. In the failing heart (right), long-term stimulation by elevated serum catecholamines (possibly in addition to other presently unidentified stimuli) results in PKA hyperphosphorylation of RyR2.10 PKA hyperphosphorylation of RyR2 causes dissociation of 3 to 4 FKBP12.6s, resulting in pathological hypersensitivity to activation by cytosolic Ca2+ in the nmol/L range.10 Phosphorylation of phospholamban (PLB) is decreased in failing hearts. The differential phosphorylation of RyR2 and PLB in the same cell may be due to local regulation by specific macromolecular signaling complexes. PKA hyperphosphorylation of RyR2 may pathologically increase SR Ca2+ release, possibly during diastole (ie, contributing to afterdepolarizations that can trigger cardiac arrhythmias). The hypothesized effects of these signaling events on SR Ca2+ content, peak SR Ca2+ release, and aberrant diastolic Ca2+ release are summarized at the bottom of the model.

IP₃R channels are activated by the second messenger IP₃, which is generated via activation of phospholipase C by either G protein–coupled receptors or receptors linked to the src family of tyrosine kinases. It is unlikely that IP₃R2s, which are about 50-fold less abundant than RyR2 in cardiomyocytes,¹⁶ can play an important role in regulating global [Ca²⁺]. More likely, IP₃R2 serves specialized functions in cardiomyocytes including (1) regulating organellar membrane permeability (including the nuclear membrane); (2) amplifying or propagating electrical signals in the heart because Purkinje fibers in the heart have the highest levels of IP₃R¹⁷ ; and (3) controlling local Ca²⁺ signaling that may play a role in regulating cell growth pathways.²

Although FKBP12 and FKBP12.6 are enzymes with cis-trans peptidyl-prolyl isomerase activity, it is unlikely that this enzymatic activity is directly involved in regulating RyR channel function.¹⁸ This is because FKBP12 and FKBP12.6 bind with nanomolar affinity to RyR and remain tightly bound in vivo. FKBP12 and FKBP12.6 enzymatic activity is based on high-affinity binding to the transition-state intermediate (twisted amide) conformation of the peptidyl-prolyl bond.¹⁹ If FKBPs catalyze the cis-trans isomerization of a peptidyl-prolyl bond in RyR, they would be released from the substrate (RyR) when the reaction went to completion (either to cis or trans). Because this does not occur in vivo, the structure of the RyR channel must prevent the peptidyl-prolyl bond from achieving either the cis or trans conformation and instead is constrained because of steric hindrance in a high-energy (unstable) intermediate. Binding of FKBP12 and FKBP12.6 lowers the energy of this unstable intermediate and stabilizes the channel structure.²⁰

If FKBP12 and FKBP12.6 remain constantly bound to RyRs, how do they play a role in regulating channel function? The answer is that binding of FKBP12 and FKBP12.6 to RyRs is physiologically regulated.¹⁰ One physiological regulator of FKBP12.6 binding is phosphorylation of RyR2 by cAMP-dependent protein kinase A (PKA), which dissociates FKBP12.6 from RyR2.¹⁰ One puzzling finding is that the serine phosphorylated by PKA (Ser2809)¹⁰ is also a substrate for CamKII,²¹ yet, unlike PKA, CamKII phosphorylation does not dissociate FKBP12.6 from the channel.¹⁰ The basis for this difference is being investigated. The functional consequence of dissociating FKBP12.6 from RyR2 is increased activity (increased open probability) of RyR2. Increased activity of RyR2 induced by dissociation of FKBP12.6 results from a leftward shift in the Ca²⁺ dependence for activation. Therefore, FKBP12.6 binding to RyR2 modulates EC coupling gain.¹⁰ EC coupling gain is defined as the amount of SR Ca²⁺ released for a given trigger (Ca²⁺ influx via the voltage-gated Ca²⁺ channel).²² There is general agreement on the essential role of FKBP12 in regulating RyR1 function as originally reported,^{14 20 23} but one group has reported no functional role for FKBP12.6 in the RyR2 complex.²⁴

Regulation of PKA phosphorylation of RyR2 and hence of the binding of FKBP12.6 to the channel seem to be under the control, at least in part, of local signaling complexes.¹⁰ It is likely that in addition to FKBP12 and FKBP12.6, 20 or more proteins are tightly associated with RyR1 and RyR2 channels (and IP₃Rs). Thus, the gigantic cytoplasmic domains of these ion channels are scaffolds for regulators of channel function.¹⁰ The intracellular Ca²⁺ release channels are macromolecular signaling complexes (Figure 1) in which multiple proteins, including kinases, phosphatases, and adaptor and anchoring proteins, are bound to specific binding domains on the enormous cytoplasmic portion of the channels.¹⁰ Each subunit of the tetrameric cardiac RyR2 has one molecule of the following tightly bound to specific sites on its cytosolic domain: FKBP12.6,²⁵ PKA catalytic and regulatory subunits, the anchoring protein mAKAP,^{10 26} protein phosphatase 1 (PP1), and protein phosphatase 2A (PP2A).¹⁰ Similarly, the nonreceptor protein tyrosine kinase fyn complexes with the type 1 IP₃R.²⁷

There are both Ca²⁺-activating²⁸ and Ca²⁺-inhibitory²⁹ sites on RyRs. Because Ca²⁺ influx via the DHPR activates RyR2 in cardiomyocytes, there must be a Ca²⁺-activating site that is accessible to influxing Ca²⁺ on the cytosolic face of the channel. There are at least 2 possibilities: this cytosolic activating Ca²⁺ site is regulated by global Ca²⁺ in the cardiomyocyte or it sees only a local Ca²⁺ signal within a restricted domain.^{30 31 32} If local Ca²⁺ signaling is controlling, then all bets are off as to what range of [Ca²⁺] is important (the Ca²⁺ concentration could be extremely high at the Ca²⁺-activating site), whereas if global Ca²⁺ is controlling, there are well-defined limits (100 nmol/L to 1 µmol/L) for the range of Ca²⁺ that regulates RyR2.

It has been argued that elevated levels of cytosolic Ca²⁺ in failing heart muscle cells activate Ca²⁺-dependent enzymes, such as calcineurin, and trigger pathological responses, such as hypertrophy.³³ However, it is highly unlikely that this type of signaling can occur on the basis of disturbances in global Ca²⁺. It has been suggested that IP₃R mediates Ca²⁺ signals that activate calcineurin in cardiomyocytes, as has been shown to be the case in T lymphocytes.³⁴ However, there is 50- to 100-fold more RyR2s than IP₃Rs in the cardiomyocyte,¹⁶ and RyR2 is obligatorily activated with each heart cycle. Thus, any IP₃-induced Ca²⁺ release in a heart muscle cell would be difficult to determine and would probably not alter global Ca²⁺ signals, because they would be swamped by RyR2-mediated Ca²⁺ release. If IP₃-gated channels regulate local Ca²⁺ signals that are not measurable in the face of huge global Ca²⁺ transients and not affected by them, then it might be possible for the IP₃R to play a role in activating Ca²⁺-dependent enzymes in the heart. Ca²⁺-activated enzymes may be constitutively active in living beating cardiomyocytes and paired with Ca²⁺-independent enzymes. IP₃Rs may also regulate membrane permeability by controlling [Ca²⁺] inside organelles, such as the nuclear membrane (IP₃Rs are present in the outer nuclear membrane).^{35 36} Many signaling pathways require the translocation of cytosolic factors (such as the nuclear factor of activated transcription or NF-AT) into the nucleus, and IP₃R in the outer nuclear membrane may be involved as a modulator of Ca²⁺-dependent membrane permeability.

A limitation toward understanding cardiac failure and arrhythmias is the inability to measure [Ca²⁺] inside the cardiomyocytes of a living beating heart in situ. A biological Ca²⁺ sensor (eg, Ca²⁺-sensitive green fluorescent protein)³⁷ expressed in cardiomyocytes and imaged with a fiber-optic catheter would provide useful information about Ca²⁺. Data from dissociated cardiomyocytes (absent extracellular matrix and cell-to-cell connections and requiring arbitrarily set SR Ca²⁺ loads) or ex vivo hearts or muscle strips are seriously limited. Isolated cardiomyocytes likely do not reflect the in vivo conditions of cells with regard to the phosphorylation status of key Ca²⁺-handling proteins. Phosphatases and kinases presumably remain active after isolation but are no longer exposed to the same regulatory conditions as myocytes in failing hearts. Cardiomyocytes in some failing hearts may be intrinsically normal, with functional impairment due, in part, to phosphorylation of signaling molecules. Once these cardiomyocytes are isolated and cultured, they could revert to normal function.

Defective regulation of RyR2 in failing hearts is associated with PKA hyperphosphorylation of the channel, resulting in dissociation of FKBP12.6 and increased sensitivity to Ca²⁺-dependent activation.¹⁰ This defective regulation is maladaptive (Figure 2), because the physiological response to PKA phosphorylation results in increased cardiac contractility due to increased EC coupling gain.¹⁰ In failing hearts, this pathway becomes overstimulated, and pathological consequences may include depletion of SR Ca²⁺ stores required for EC coupling (although depletion of SR Ca²⁺ stores in failing hearts has not been demonstrated yet) as well as aberrant release of SR Ca²⁺ during diastole, which may serve as a trigger for fatal cardiac arrhythmias.¹⁰ These studies provide a molecular basis for understanding why and how ß-adrenergic blockade is beneficial to patients with heart failure.¹⁰ RyR2 is defective because of PKA hyperphosphorylation in failing hearts, but ß-adrenergic blockade restores the channel function toward normal.¹⁰ An explanation for the lack of positive inotropic affect of ß-adrenergic agonists on failing hearts may be that an important substrate, RyR2, is already PKA-hyperphosphorylated and cannot be further phosphorylated.¹⁰ It is likely that no one molecule will account for all of the defects in signaling that cause heart failure, and, similarly, it is highly unlikely that therapy targeted at a single molecule will be well tolerated and beneficial to patients with heart failure.

	Acknowledgments

 
This work was supported by grants from the National Institutes of Health, American Heart Association, and Richard and Lynne Kaiser Family Foundation. The author acknowledges input from colleagues and laboratory members and thanks Barbara Ehrlich, W. Jonathan Lederer, Robert Kass, Donald Bers, and Susan Hamilton for helpful discussions.

Received March 29, 2000; accepted May 12, 2000.

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