Critical Amino Acid Residues Determine the Binding Affinity and the Ca2+ Release Efficacy of Maurocalcine in Skeletal Muscle Cells

Estève, É.; Smida-Rezgui, Sophia; Sárközi, Sándor; Szegedi, Csaba; Regaya, Imed; Chen, Lili; Altafaj, Xavier; Rochat, H.; Allen, Paul D.; Pessah, Isaac N.; Marty, Isabelle; Sabatier, Jean‐Marc; Jóna, István; Waard, Michel De; Ronjat, Michel

doi:10.1074/jbc.m305798200

Cited by 43 publications

(72 citation statements)

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“…We also introduce the first biochemical evidence that MCa and domain A of the DHPR ␣ 1 subunit interact with identical sequences on RyR1. In view of the important effects of MCa on RyR1 gating properties (13,14), the RyR1 sequences that we identified in this report ought to play an important function in RyR1 calcium channel behavior. The fact that domain A of the II-III loop of DHPR binds onto the same RyR1 sequences re-opens the question of the role of the domain A in the control of RyR1 calcium channel activity in the context of the DHPR/RyR1 complex.…”

Section: Discussionmentioning

confidence: 82%

“…Peptide Synthesis-Peptides were synthesized as described previously (14,19), with the addition of an exogenous biotin on the Cterminal amino acid of (i) MCa synthetic peptide, (ii) peptide A sk and peptide C sk corresponding to residues Thr 671 -Lys 690 and Glu…”

Section: Methodsmentioning

confidence: 99%

“…These two toxins present some amino acid sequence homology with the domain A of DHPR ␣ 1 subunit, and structural studies strongly suggest that their ␤-sheet structure could mimic that of the domain A (15,16). In a previous work, we demonstrated that nanomolar concentrations of MCa induces a dramatic conformational change of RyR1, witnessed by the increase in [ 3 H]ryanodine binding (7-fold) and the induction of long lasting channel openings (13,14). The observed homologies in amino acid sequences and in three-dimensional solution structure have prompted different authors to make the hypothesis that imperatoxin A and MCa could share a common binding site with the domain A of the DHPR ␣ 1 subunit on the RyR1.…”

mentioning

confidence: 97%

“…As part of the search for molecules able to strongly modify RyR1 properties, toxins isolated from scorpion venoms have been described as the most active effectors of RyR1. Among them, imperatoxin A and maurocalcine (MCa) have been extensively characterized both in terms of their effects on RyR1 and their three-dimensional structure (11)(12)(13)(14)(15)(16). These two toxins present some amino acid sequence homology with the domain A of DHPR ␣ 1 subunit, and structural studies strongly suggest that their ␤-sheet structure could mimic that of the domain A (15,16).…”

mentioning

confidence: 99%

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Maurocalcine and Domain A of the II-III Loop of the Dihydropyridine Receptor Cav 1.1 Subunit Share Common Binding Sites on the Skeletal Ryanodine Receptor

Altafaj

Cheng

Estève

et al. 2005

Journal of Biological Chemistry

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Maurocalcine is a scorpion venom toxin of 33 residues that bears a striking resemblance to the domain A of the dihydropyridine voltage-dependent calcium channel type 1.1 (Ca v 1.1) subunit. This domain belongs to the II-III loop of Ca v 1.1, which is implicated in excitation-contraction coupling. Besides the structural homology, maurocalcine also modulates RyR1 channel activity in a manner akin to a synthetic peptide of domain A. Because of these similarities, we hypothesized that maurocalcine and domain A may bind onto an identical region(s) of RyR1. Using a set of RyR1 fragments, we demonstrate that peptide A and maurocalcine bind onto two discrete RyR1 regions: fragments 3 and 7 encompassing residues 1021-1631 and 3201-3661, respectively. The binding onto fragment 7 is of greater importance and was thus further investigated. We found that the amino acid region 3351-3507 of RyR1 (fragment 7.2) is sufficient for these interactions. In skeletal muscle cells, the activation of the dihydropyridine receptor (DHPR) 1 induces, through the ryanodine receptor (RyR1), a massive release of the calcium stored in the sarcoplasmic reticulum. The bi-directional communication between RyR1 and DHPR (i.e. orthograde and retrograde signals) has been shown to be enabled by the physical interactions of the two Ca 2ϩ channels (1-4). The DHPR ␣ 1 subunit forms the pore region, carries the voltage sensitivity of the channel, and is also directly involved in the functional coupling of the DHPR with RyR1 (2, 5). Indeed, the cytoplasmic loop linking domains II and III of the ␣ 1 subunit has been proposed to be responsible for the mechanical coupling between the DHPR and the RyR1 (6, 7). Within this loop, two regions (domains A and C) have been shown to regulate ryanodine binding and channel gating of RyR1 in vitro (8).RyR1 activity is regulated in vitro by a number of chemical compounds such as ATP, Ca 2ϩ , Mg 2ϩ , and proteins such as calmodulin and FK506-binding protein (FKBP12) (9, 10). Nevertheless, due to (i) the extremely large size of RyR1, (ii) the small number of high affinity effectors, and (iii) the absence of atomic resolution structure, the mapping of the functional sites of RyR1 is still far from completion. As part of the search for molecules able to strongly modify RyR1 properties, toxins isolated from scorpion venoms have been described as the most active effectors of RyR1. Among them, imperatoxin A and maurocalcine (MCa) have been extensively characterized both in terms of their effects on RyR1 and their three-dimensional structure (11-16). These two toxins present some amino acid sequence homology with the domain A of DHPR ␣ 1 subunit, and structural studies strongly suggest that their ␤-sheet structure could mimic that of the domain A (15, 16). In a previous work, we demonstrated that nanomolar concentrations of MCa induces a dramatic conformational change of RyR1, witnessed by the increase in [ 3 H]ryanodine binding (7-fold) and the induction of long lasting channel openings (13,14). The observed homologies in amino...

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Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Maurocalcine and Domain A of the II-III Loop of the Dihydropyridine Receptor Cav 1.1 Subunit Share Common Binding Sites on the Skeletal Ryanodine Receptor

Altafaj

Cheng

Estève

et al. 2005

Journal of Biological Chemistry

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“…Cette hypothèse était largement renforcée par le fait que le site d'interaction de la maurocalcine sur RyR1 est localisé dans une zone du cytoplasme [7]. La démonstration que la maurocalcine était effectivement un CPP est venue des observations suivantes : (1) l'application extracellulaire du peptide à des myotubes induit une libération calcique quasi instantanée [8] ; et (2) la greffe d'une protéine streptavidine fluorescente sur la maurocalcine biotinylée permet sa translocation intracellulaire [5]. Par ailleurs, la maurocalcine partage en commun avec les autres CPP la propriété d'être un peptide basique dont de nombreux acides aminés sont chargés positivement (11 sur 33).…”

Section: Peptides De Pénétration Cellulaire Et Mécanisme D'entrée Celunclassified

Administration de molécules actives dans les cellules

Poillot

Waard

2011

Med Sci (Paris)

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Pharmacology of ryanodine receptors and Ca²⁺‐induced Ca²⁺ release

Thomas

Williams

2012

WIREs Membr Transp Signal

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Ryanodine receptors (RyR) are cation-selective, ligand-modulated, ion channels that provide a pathway for the regulated release of Ca 2+ from intracellular reticular storage organelles to initiate a wide variety of cellular processes. In addition to regulation by endogenous ligands, the function of RyR can be altered by many pharmacological agents. Some of these have been used to establish the contribution of RyR-mediated Ca 2+ release to diverse signaling processes. Altered RyR function also plays a role in the development of diseases of both skeletal and cardiac muscles, hence both new and established compounds have potential as RyR-focussed therapeutic agents. efflux from the sarco/endoplasmic reticulum (SR/ER), and are responsible for triggering numerous Ca 2+ -activated physiological processes, the most widely studied of which is excitation-contraction coupling (ECC). This process occurs in the myocyte and describes the translation of the electrical impulse into physical contraction of the cell, and tissuespecific expression of RyR1 or RyR2 isoforms in skeletal or cardiac muscles, respectively, is essential for this. 1 The mechanism of activation for each isoform is different, the former being activated by the virtue of direct physical coupling with the L-type Ca 2+ channel, and the latter by Ca 2+ -induced Ca 2+ release (CICR). 1 Both are immense tetrameric channels (2.2MDa), composed of a relatively small pore region and a large cytoplasmic domain that serves to interact with a comprehensive set of accessory proteins thought to modulate channel function (reviewed elsewhere 2,3 ). Dysfunction of these RyRs, most commonly manifest as enhanced Ca 2+ release at rest (skeletal muscle) or during diastole (cardiac muscle), appears to be the fundamental mechanism underlying several genetic or acquired * Correspondence to: williamsaj9@cardiff.ac.uk Wales Heart Research Institute, Department of Medicine, Cardiff University, Cardiff, UK syndromes. Malignant hyperthermia (MH) and central core disease (CCD) are disorders of skeletal muscle, which cause muscle rigidity, respiratory and metabolic acidosis, and a dramatic rise in body temperature in response to halogenated anesthetics, and hypotonia/motor deficiencies, respectively, and are caused by mutations in RyR1. 4 In cardiac muscle, RyR2 mutations lead to catecholaminergic polymorphic ventricular tachycardia (CPVT1) and other cardiac arrhythmias. [5][6][7] Defective regulation of this channel has also been implicated in the development of arrhythmias in heart failure (HF). 8Investigation of the mechanisms behind channel dysfunction has been a steadily growing area of research over the last decade, and many of these studies have been in native or whole cell systems. As a result pharmacological tools have been required to evaluate or modulate RyR function in these disease models.Many articles have reviewed the basic pharmacology of the RyR, 9-12 and while these have been useful, listing the myriad compounds which affect channel function (ranging from its namesake r...

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Critical Amino Acid Residues Determine the Binding Affinity and the Ca2+ Release Efficacy of Maurocalcine in Skeletal Muscle Cells

Cited by 43 publications

References 27 publications

Maurocalcine and Domain A of the II-III Loop of the Dihydropyridine Receptor Cav 1.1 Subunit Share Common Binding Sites on the Skeletal Ryanodine Receptor

Maurocalcine and Domain A of the II-III Loop of the Dihydropyridine Receptor Cav 1.1 Subunit Share Common Binding Sites on the Skeletal Ryanodine Receptor

Administration de molécules actives dans les cellules

Pharmacology of ryanodine receptors and Ca²⁺‐induced Ca²⁺ release

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Critical Amino Acid Residues Determine the Binding Affinity and the Ca2+ Release Efficacy of Maurocalcine in Skeletal Muscle Cells

Cited by 43 publications

References 27 publications

Maurocalcine and Domain A of the II-III Loop of the Dihydropyridine Receptor Cav 1.1 Subunit Share Common Binding Sites on the Skeletal Ryanodine Receptor

Maurocalcine and Domain A of the II-III Loop of the Dihydropyridine Receptor Cav 1.1 Subunit Share Common Binding Sites on the Skeletal Ryanodine Receptor

Administration de molécules actives dans les cellules

Pharmacology of ryanodine receptors and Ca2+‐induced Ca2+ release

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Pharmacology of ryanodine receptors and Ca²⁺‐induced Ca²⁺ release