Calcium Signalling: The Next Generation

Structural and functional interactions within ryanodine receptor Monika Seidel*, F. Anthony Lai* and Spyros Zissimopoulos*1 *Wales Heart Research Institute, Cardiff University School of Medicine, Institute of Molecular and Experimental Medicine, Heath Park, Cardiff CF14 4XN, U.K.

Biochemical Society Transactions

Abstract The ryanodine receptor/Ca2 + release channel plays a pivotal role in skeletal and cardiac muscle excitation– contraction coupling. Defective regulation leads to neuromuscular disorders and arrhythmogenic cardiac disease. This mini-review focuses on channel regulation through structural intra- and inter-subunit interactions and their implications in ryanodine receptor pathophysiology.

Introduction Ryanodine receptors (RyR), high-conductance cationselective channels, mediate Ca2 + release from the sarcoplasmic reticulum (SR) essential for muscle contraction. The three known mammalian isoforms display a high degree of similarity in the peptide sequence and three-dimensional structure. Functional channels are homotetramers regulated by complex interactions between subunits, accessory proteins and other molecules including ATP, Ca2 + and Mg2 + . Abnormalities in channel function associated with RyR mutations result in life-threatening pathologies such as malignant hyperthermia (MH), central core disease (CCD) and catecholaminergic polymorphic ventricular tachycardia (CPVT).

RyR regulation by intra- and inter-subunit interactions Interactions between N-terminal domains The N-terminal inter-subunit self-association has recently emerged as a critical structure–function parameter in the regulation of the channel. Computational docking of the N-terminus atomic structure (residues 1–559) into the (low resolution) full-length RyR1 cryo-electron microscopy map placed four N-terminal domains next to each other forming a vestibule around the four-fold axis [1]. Nterminus localization was somewhat displaced in the open versus the closed state suggesting that channel opening coincides with altered inter-subunit interactions [2]. Empirical evidence from a combination of yeast twoKey words: Ca2 + release channel, excitation–contraction coupling, inter-domain interactions, oligomerization, pathophysiology, ryanodine receptor. Abbreviations: ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CaMBD, calmodulin-binding domain; CaMLD, calmodulin-like domain; CCD, central core disease; CPVT, catecholaminergic polymorphic ventricular tachycardia; FRET, fluorescence resonance energy transfer; HF, heart failure; MH, malignant hyperthermia; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; TM, transmembrane; WT, wild-type. 1 To whom correspondence should be addressed (email [email protected]).

Biochem. Soc. Trans. (2015) 43, 377–383; doi:10.1042/BST20140292

hybrid, co-immunoprecipitation, chemical cross-linking and gel filtration assays has indicated that the RyR2 Nterminus (residues 1–906) possesses the intrinsic ability to oligomerize, enabling apparent tetramer formation that is further stabilized by endogenous disulfide bonds [3]. Nterminus tetramerization is conserved in RyR1/3 and also in the related inositol trisphosphate receptor [4]. Disruption of N-terminal inter-subunit interactions within RyR2 increased channel activity at low Ca2 + concentrations assessed by ryanodine binding and single channel measurements, suggesting that N-terminus tetramerization is involved in RyR2 channel closure [3].

Interactions between N-terminal and central domains Ikemoto and colleagues have built a hypothesis for RyR amino-terminal/central domain association based on the use of short synthetic peptides corresponding to these regions. Initially, it was shown that RyR2-specific DP1-2c (residues 601–639) and the shorter DP1 peptide (601–620) induced rapid Ca2 + release from, and enhanced ryanodine binding to cardiac SR, while the corresponding RyR1 DP1-2s (590–628) and (identical) DP1 (590–609) peptides had a modest effect on skeletal SR [5,6]. It was subsequently shown that central domain peptides (RyR1-specific DP4 (2442–2477) and RyR2specific DPc10 (2460–2495)) induced hyper-activation and hyper-sensitization effects for both RyR isoforms assessed by SR Ca2 + flux, ryanodine binding assays and single channel recordings [5,7]. Those findings were further supported by more physiological experiments performed on skinned and saponin-permeabilized skeletal muscle fibres, where it was found that DP4 enhanced SR Ca2 + release and contraction and increased the frequency of Ca2 + sparks [8,9]. Similarly, DPc10 increased Ca2 + spark frequency in cardiomyocytes while it decreased Ca2 + transients and cell shortening due to SR Ca2 + leak [10,11]. Interestingly, DP4 was reported to have no effect on RyR3 suggesting that selective RyR1 stabilization by the N-terminal/central domain association  C The

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may account for reduced Ca2 + -induced Ca2 + release activity of RyR1 compared with RyR3 [12]. The use of a conformation-sensitive fluorescent probe incorporated into RyR1 at the DP4-binding site (or RyR2 at DPc10-binding site) revealed that peptide-induced channel activation coincides with a local conformation change and an increase in the inter-domain distance [10,13,14]. Labelling of the DP4 (or DPc10) conjugated fluorescent probe took place in the 150 kDa N-terminal calpain-cleaved RyR fragment providing biochemical evidence for N-terminal interaction with the central domain [10,13]. Surprisingly in similar chemical cross-linking experiments N-terminal peptides were unable to label the central domain. The DP4-binding region was further mapped to a 51 kDa N-terminal-most RyR1 fragment recognized by antibody against residues 324–351 [15]. The N-terminal/central domain interaction is most probably inter-subunit rather than within a single subunit shown by fluorescence resonance energy transfer (FRET) experiments [16]. The above results led to the hypothesis that a close contact between the amino-terminus and central domain stabilizes the closed state of RyR. Addition of a domain-specific peptide produces partial unzipping of the interacting regions and results in hyper-activation of the channel. Additional or alternative interactions are also likely to exist. A RyR1 N-terminal fragment (residues 281–620) was found to interact with native RyR1, and the binding sites were mapped to two fragments (residues 799–1172 and 2937–3225) that do not contain the DP4 sequence [17]. Further evidence for interactions between the RyR1 N-terminal region and central domains was provided by the identification of interand intra-subunit disulfide bonds involving Cys-36, 2326, 2363 and 3635 [18–20]. It has also been proposed that interaction of the second SPRY domain (residues 1085–1208) with the central domain (residues 3471–3500 containing an alternatively spliced sequence of five residues) stabilizes the closed conformation of the RyR1 channel [21,22]. In addition, computational modelling and FRET studies have suggested that two structurally homologous domains (residues 850– 1056 and 2733–2940) interact with each other across adjacent RyR1 subunits [23].

Interactions between central domains The use of synthetic peptides and chemical cross-linking has indicated that the binding site (RyR2 residues 2114– 2149) of the cardioprotective drug JTV519 (also known as K201) interacts with a downstream sequence (2234– 2750) [24]. It was further shown that this interaction becomes tighter upon DPc10-induced channel activation and the addition of JTV519 or JTV519-binding peptide restores RyR2 N-terminal/central domain interactions [24], and reverses DP4-induced activation of RyR1 [5]. Based on these findings, it was proposed that the N-terminal/central domain and central/central domain associations are coupled in a reciprocal manner to regulate RyR channel activity.  C The

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Interactions between central and C-terminal domains The calmodulin-binding domain (CaMBD) encompassing RyR1 residues 3614–3643 has been recognized as an important self-regulatory domain of channel function. It was shown that this peptide increased SR Ca2 + release, ryanodine binding and RyR1 channel activity, as well as increased Ca2 + spark frequency in skeletal muscle fibres [25–28]. The CaMBD-binding partner was proposed to be a sequence (residues 4064–4210) with structural similarities to calmodulin and an intrinsic ability to bind Ca2 + [29]. Consistently, chemical cross-linking assays identified a 96 kDa RyR1 C-terminal fragment recognized by an antibody against residues 4114–4142 as the CaMBDbinding site, while fluorescence quenching assays suggested a Ca2 + -dependent interaction [30]. It was proposed that an inter-domain interaction occurs between CaMBD and the calmodulin-like domain (CaMLD), involved in Ca2 + dependent channel activation. Interestingly, CaMBD peptide at high concentrations or its C-terminal part was found to be inhibitory [25,28], suggesting that it may interact with two functionally discrete RyR domains. Another potential CaMBD-interacting site may lie further upstream since Cys3635 is involved in inter-subunit disulfide bond formation with Cys-2326 and/or Cys-2363 [18–20].

Interactions between C-terminal domains A FRET study, which used a series of truncated RyR2 cytoplasmic fragments in combination with C-terminal constructs encompassing the channel pore, has shown that residues 3722–4610 (I-domain) were critical for restoring functionality to hybrid channels [31]. Caffeine-induced Ca2 + release was accompanied by an increase in FRET efficiency implying a conformation change within interacting domains. Based on these findings, it was proposed that discrete sequences located in the I-domain dynamically interact with one another to functionally integrate cytoplasmic modulatory events with the transmembrane (TM) assembly [31]. A peptide within the I-domain (residues 4090–4123) was also shown to induce Ca2 + leak and increase Ca2 + spark frequency in cardiomyocytes, although its binding partner was not identified [32]. It was suggested that the I-domain is allosterically coupled to the N-terminal/central domain interface in a manner that disruption of the latter triggers changes in the former. In addition, a 96 kDa RyR1 fragment containing the I-domain was found by chemical cross-linking assays to bind the M7b-M8 cytosolic loop (residues 4820–4841) within the TM assembly [33]. A peptide corresponding to the M7b-M8 linker disrupted the interaction between the two domains and activated the channel in a Ca2 + -dependent way. Other studies proposed additional or alternative interacting partners for the M7b-M8 linker, including domain M10 within the same subunit and domain M8 from an adjacent subunit, as well as the extreme C-terminal tail [34,35]. Taken together the above studies suggest that extensive interactions within the RyR carboxyl-

Calcium Signalling: The Next Generation

terminus transduce cytoplasmic activation signals to the channel pore. The membrane-spanning domains within the RyR Cterminus are capable of self-association and constitute the channel pore. Proteolysis of native RyR1 yielded a smaller tetrameric complex composed of the C-terminal 76 kDa fragment that retained cation-conducting channel properties assessed by single channel recordings [36]. A truncated RyR1 containing the C-terminal 1030 amino acids was found to form an ion channel with conductance comparable to that of the full-length protein [37,38]. Cells expressing RyR1 or RyR2 C-terminal fragments had a higher resting Ca2 + concentration and smaller Ca2 + stores [31,37,38]. These findings indicate that the RyR carboxyl-terminus forms a Ca2 + conduction pore that is constitutively open. The cytoplasmic C-terminal tail of the protein is crucial for the assembly of a tetrameric functional channel since truncated RyR1 lacking the last 15 residues was shown to form an inactive channel [39]. It was also demonstrated that the RyR2 C-terminal tail (residues 4867–4967) is capable of tetramerization with the last 15 amino acids necessary for the oligomerization process [40].

Implications for RyR1 neuromuscular disorders The search for critical domains involved in RyR1-related pathologies was facilitated by the fact that mutations seem to cluster within three definable regions, amino-terminus, central and carboxyl-terminus. As discussed earlier, the central domain DP4 peptide results in hyper-activation and hyper-sensitization of RyR1 mimicking the effect of MH mutations. Importantly, a single amino acid substitution within the DP4 peptide corresponding to a MH mutation (R2458C) was shown to abolish its activating effects [5,9]. These findings led Ikemoto and co-workers to suggest that the N-terminal/central domain interaction is disrupted in MH leading to increased channel activity. This hypothesis is also supported by the study of pig RyR1 with a naturally occurring MH mutation (R615C). MH channels displayed increased activity compared with wild-type (WT) and exhibited no substantial activation upon DP4 treatment unlike WT RyR1 [41]. The inability of DP4 to activate pig MH RyR1 implied that hyper-sensitization of the mutant channel is a consequence of impaired N-terminal/central domain association that has already occurred in MH RyR1. It was also reported that dantrolene, the only available and clinically approved drug for treatment against MH, is able to stabilize RyR1 by reversing DP4-induced channel activation and preventing N-terminal/central domain unzipping [15]. The localization of the N-terminus in the full-length RyR1 map by computational docking suggested that most N-terminal mutations affect inter-domain interactions rather than binding of ligands and/or accessory proteins [1]. Based on N-terminus positioning in the open compared with the closed RyR1 state, it was recently proposed that N-terminus

interaction between neighbouring subunits governs channel activity [2]. Van Petegem and colleagues suggested that this inter-subunit interface becomes disrupted in the presence of MH-associated mutations either directly or indirectly through allosteric effects. Defective inter-domain interactions within the C-terminus have also been implicated in RyR1 pathophysiology. It was shown that the activating properties of two peptides (residues 4114–4142 and 4820–4841) corresponding to C-terminal interacting domains, were substantially reduced after a single amino acid substitution representing a MH mutation was introduced to each one (R4137S and L4837V, respectively) [33]. The peptide-based studies represent an elegant approach to study RyR1 regulation and to correlate mutations with functional abnormalities but they do have limitations. For example, different amino acid substitutions representing different MH mutations within a given peptide had a variable impact on the peptide’s activating properties with some modestly different from WT [33,42]. Although these findings might imply that there is some correlation between mutation site and severity of MH phenotype, this has not been clinically observed.

Implications for RyR2 arrhythmogenic cardiac disease Defective N-terminal inter-subunit interactions within RyR2 have been implicated in inherited arrhythmogenic cardiac disease. The pro-arrhythmic L433P mutation was recently found to disrupt N-terminus self-association thereby conferring an altered sensitivity to Ca2 + activation [43]. Cells expressing the mutant RyR2 displayed prolonged Ca2 + transients and reduced Ca2 + store content compared with WT, consistent with a defective channel closure mechanism. Importantly, dantrolene treatment promoted L433P N-terminus selfassociation and normalized cellular Ca2 + handling [43]. Several studies have also indicated that N-terminal/central domain unzipping underlies channel dysfunction and diastolic SR Ca2 + leak in CPVT. A single amino acid substitution within the DPc10 peptide representing a CPVT mutation (R2474S) abolished its activating effects [7,11]. Moreover, cardiomyocytes from RyR2 R2474S transgenic mice exhibited higher Ca2 + spark frequency and lower SR Ca2 + content compared with WT due to defective Nterminal/central domain interactions, which were further aggravated following stimulation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase [44]. DPc10 peptide mimicked the phenotype of knockin channels in WT cardiomyocytes but had no effect on (cAMP-treated) transgenic cardiomyocytes suggesting N-terminal/central domain dissociation in mutant RyR2 [44]. Dantrolene was able to reverse inter-domain unzipping and Ca2 + spark frequency induced by DPc10 in WT and cAMP in R2474S channels, and prevented exercise-induced ventricular tachycardia in R2474S knockin mice [44,45]. Similar results were reported  C The

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Figure 1 RyR intra- and inter-subunit interactions Schematic representation of inter-domain interactions within a single subunit or across subunits within the RyR tetramer. For simplicity, a single full-length subunit is depicted (in light blue) and only contact sites from an adjacent subunit are shown (in light grey).

for RyR2 knockin mice carrying the S2246L CPVT mutation suggesting cross-talk between N-terminal/central domain association and the JTV519-binding domain [46]. Notably, the extent of RyR2 inter-domain unzipping was variable and depended on the mutation, i.e. the R2474S mutation was reported to induce partial unzipping that was aggravated by β-adrenergic agonists, while the S2246L mutation was shown to result in a fully unzipped state irrespective of β-adrenergic stimulation [44,46]. The N-terminal/central domain interaction was suggested to couple to other interfaces, namely the JTV519-binding domain and CaMBD/CaMLD, both of which were suggested to be defective in the presence of arrhythmia-associated mutations [46–48]. It was shown that the therapeutic effect of JTV519 in CPVT is associated with correction of disrupted domain–domain interactions within the central portion of the protein, which in turn restores the defective contact  C The

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between N-terminal and central domains [46]. Similarly, proarrhythmic mutation-induced N-terminal/central domain unzipping was proposed to increase the CaMBD/CaMLD association thereby triggering partial dissociation of calmodulin and channel hyperactivity [47,48]. Disrupted interactions between other domains have also been implicated in the development of CPVT. Using a protein complementation approach, it was found that upon caffeine stimulation overlapping N-terminal and C-terminal RyR2 fragments carrying CPVT mutations (S2246L/N4104K and R4497C respectively) exhibited abnormal Ca2 + release and altered I-domain interactions compared with WT [49]. Interestingly, peptide-induced defective interactions within the I-domain and channel function could not be restored by JTV519 treatment [32]. Consistently, JTV519 administration failed to prevent ventricular tachycardia in R4496C knockin mice [50].

Calcium Signalling: The Next Generation

Defective inter-domain interactions within RyR2 have also been implicated in the pathogenesis of heart failure (HF). In a canine model of pacing-induced HF, RyR2 channels were leaky due to excessive oxidation accompanied by N-terminal/central domain unzipping, which could be prevented by antioxidant treatment [51]. It was further shown that cAMP- and DPc10-induced Ca2 + leak in normal SR as well as spontaneous Ca2 + leak in failing SR is reversed by JTV519 and dantrolene by restoring N-terminal/central domain association [10,52]. Similar to central domain DPc10, two other peptides (N-terminal 163– 195 and I-domain 4090–4123) were also found to induce HF phenotype in dog cardiomyocytes [32]. Interestingly, JTV519 was only able to alleviate the action of the Nterminal but not the I-domain peptide, suggesting that it prevents N-terminal/central domain unzipping and the secondary I-domain conformational changes but it is ineffective when defective interactions are induced directly within the I-domain. The allosteric coupling between the N-terminal/central domain interface and CaMBD was also shown to be defective in HF, leading to reduced calmodulin binding and channel dysregulation [47,53]. The above studies indicate that therapeutic interventions to correct defective inter-domain interactions within RyR2 could prevent the development of cardiac disease. JTV519 and dantrolene hold great promise but may not be always effective as shown for the former. Of note, unlike RyR1 normal WT RyR2 does not bind dantrolene in spite of the fact that the RyR1 dantrolene-binding site (residues 590–609) is conserved in RyR2 (601–620) [54,55]. Moreover, an antibody raised against a peptide (DP1 sequence) matching the dantrolenebinding site recognizes intact RyR1 but not RyR2 suggesting that this site is inaccessible in intact RyR2. Thus, it seems that the dantrolene-binding site is conformation-sensitive and becomes accessible in failing or mutant RyR2, stabilizing inter-domain interactions and channel function. In agreement with the conformation-sensitive RyR2 binding mechanism, dantrolene was shown to prevent arrhythmogenic calcium release in HF without compromising systolic function [56]. The fact that dantrolene does not alter normal RyR2 and systolic cardiac function, but affects only the diseased heart is of particular importance for its potential clinical application to attenuate arrhythmias.

Final remarks The RyR large size and membrane topology hampers determination of its three-dimensional crystal structure. The information we have obtained so far reveals dynamic and complex molecular interactions within the channel (Figure 1). The combined implementation of biochemical, functional and structural techniques as well as the use of animal models will help to elucidate the complex relationship between channel structure and its function. The detailed understanding of RyR channel regulation is prerequisite for the development of pharmacological measures to treat life-threatening cardiac and skeletal muscle pathologies.

Funding This work was supported by a British Heart Foundation Fellowship [FS/08/063 (to S.Z.)].

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Calcium Signalling: The Next Generation

53 Ono, M., Yano, M., Hino, A., Suetomi, T., Xu, X., Susa, T., Uchinoumi, H., Tateishi, H., Oda, T., Okuda, S. et al. (2010) Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca(2 + ) release in heart failure. Cardiovasc. Res. 87, 609–617 CrossRef PubMed 54 Paul-Pletzer, K., Yamamoto, T., Bhat, M., Ma, J., Ikemoto, N., Jimenez, L., Morimoto, H., Williams, P. and Parness, J. (2002) Identification of the dantrolene binding sequence of the skeletal muscle ryanodine receptor. J. Biol. Chem. 277, 34918–34923 CrossRef PubMed

55 Paul-Pletzer, K., Yamamoto, T., Ikemoto, N., Jimenez, L., Morimoto, H., Williams, P., Ma, J. and Parness, J. (2005) Probing a putative dantrolene-binding site on the cardiac ryanodine receptor. Biochem. J. 387, 905–909 CrossRef PubMed 56 Maxwell, J.T., Domeier, T.L. and Blatter, L.A. (2012) Dantrolene prevents arrhythmogenic Ca2 + release in heart failure. Am. J. Physiol. Heart Circ. Physiol. 302, H953–H963 CrossRef PubMed Received 4 November 2014 doi:10.1042/BST20140292

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Structural and functional interactions within ryanodine receptor.

The ryanodine receptor/Ca2+ release channel plays a pivotal role in skeletal and cardiac muscle excitation-contraction coupling. Defective regulation ...
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