Single channel activity of the ryanodine receptor calcium release channel is modulated by FK‐506

Ahern, Gerard P.; Junankar, Pauline R.; Dulhunty, Angela F.

doi:10.1016/0014-5793(94)01001-3

Cited by 137 publications

(103 citation statements)

References 31 publications

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“…Interestingly, there is a Val-Pro-Leu-Val motif (amino acids 4594 -4597 for human RyR2) within putative transmembrane segment M6 (nomenclature of the 10TM model (56)), which could constitute part of the FKBP-binding core. Notably, the specific residue Pro-4595 was initially proposed to be involved in FKBP binding, based on the fact that FKBP has a peptidyl-prolyl cis-trans isomerizing activity and that its dissociation destabilizes the channel and results in appearance of sub-conductance states (14,23,24). Consistent with this, it has also been suggested that proline residues contained within ␣-helical transmembrane segments are involved in conformational changes within transmembrane domains of ion channels, transport proteins and G-protein-coupled receptors (57,58).…”

Section: Discussionmentioning

confidence: 99%

“…Given the profound effects of FKBP on both the channel activity and conductance of the RyR and its peptidyl-prolyl cis-trans isomerizing activity, it was suggested that FKBP binds to Pro-4595 (numbering given for the human RyR2), a residue located within a hydrophobic, predicted transmembrane domain at the RyR C terminus (14,23,24). Furthermore, it was proposed that the FKBP-binding site may reside in, or near, the conduction pore of the channel, because FKBP12 binding to RyR1 was found to be voltage-dependent in single channel electrophysiological experiments (25).…”

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confidence: 99%

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Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain

Zissimopoulos

Lai

2005

Journal of Biological Chemistry

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The ryanodine receptor-calcium release channel complex (RyR) plays a pivotal role in excitation-contraction coupling in skeletal and cardiac muscle. RyR channel activity is modulated by interaction with FK506-binding protein (FKBP), and disruption of the RyR-FKBP association has been implicated in cardiomyopathy, cardiac hypertrophy, and heart failure. Evidence for an interaction between RyR and FKBP is well documented, both in skeletal muscle (RyR1-FKBP12) and in cardiac muscle (RyR2-FKBP12.6), however definition of the FKBP-binding site remains elusive. Early reports proposed interaction of a short RyR central domain with FKBP12/12.6, however this site has been questioned, and recently an alternative FKBP12.6 interaction site has been identified within the N-terminal half of RyR2. In this study, we report evidence for the human RyR2 C-terminal domain as a novel FKBP12.6-binding site. Using competition binding assays, we find that short C-terminal RyR2 fragments can displace bound FKBP12.6 from the native RyR2, although they are unable to exclusively support interaction with FKBP12.6. However, expression of a large RyR2 C-terminal construct in mammalian cells encompassing the pore-forming transmembrane domains exhibits rapamycin-sensitive binding specifically to FKBP12.6 but not to FKBP12. We also obtained some evidence for involvement of the RyR2 N-terminal, but not the central domain, in FKBP12.6 interaction. Our studies suggest that a novel interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a central role in the modulation of this critical ion channel.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain

Zissimopoulos

Lai

2005

Journal of Biological Chemistry

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“…Under physiological conditions (i.e., the absence of immunosuppressive drugs), FKBPs are though to bind to RyRs with high affinity and stabilize the closed state of the channel (Ahern et al 1994;Brillantes et al 1994;McCall et al 1996;Ahern et al 1997;Marx et al 1998;Marx et al 2001). Removal of FKBP12, by preventing rebinding with an immunosuppressive drug or as the result of a genetic FKBP deficiency leads to greater open probability of the channel and longer mean open times (Ahern et al 1997;Marx et al 1998;Shou et al 1998).…”

Section: Calsequestrinmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

655

572

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Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

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“…Skeletal SR was isolated from the back and leg muscles of New Zealand White rabbits, and heavy SR was collected from the 35-45% (w v À1 ) interface of a discontinuous sucrose gradient, centrifuged and resuspended (Ahern et al, 1994). Cardiac SR was prepared from sheep heart (Chamberlain & Fleischer, 1988;Laver et al, 1995).…”

Section: Isolation Of Sr Vesiclesmentioning

confidence: 99%

Functional implications of modifying RyR‐activating peptides for membrane permeability

Dulhunty

Cengia

Young

et al. 2005

British J Pharmacology

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1 Our aim was to determine whether lipoamino acid conjugation of peptides that are high-affinity activators of ryanodine receptor (RyR) channels would (a) render the peptides membrane permeable, (b) alter their structure or (a) reduce their activity. The peptides correspond to the A region of the II-III loop of the skeletal dihydropyridine receptor. 2 The lipoamino acid conjugation increased the apparent permeability of the peptide across the Caco-2 cell monolayer by up to B20-fold. 3 Nuclear magnetic resonance showed that the a-helical structure of critical basic residues, required for optimal activation of RyRs, was retained after conjugation. 4 The conjugated peptides were more effective in enhancing resting Ca 2 þ release, Ca 2 þ -induced Ca 2 þ release and caffeine-induced Ca 2 þ release from isolated sarcoplasmic reticulum (SR) than their unconjugated counterparts, and significantly enhanced caffeine-induced Ca 2 þ release from mechanically skinned extensor digitorum longus (EDL) fibres. 5 The effect of both conjugated and unconjugated peptides on Ca 2 þ release from skeletal SR was 30-fold greater than their effect on either cardiac Ca 2 þ release or on the Ca 2 þ Mg 2 þ ATPase. 6 A small and very low affinity effect of the peptide in slowing Ca 2 þ uptake by the Ca 2 þ , Mg 2 þ ATPase was exacerbated by lipoamino acid conjugation in both isolated SR and in skinned EDL fibres. 7 The results show that lipoamino acid conjugation of A region peptides increases their membrane permeability without impairing their structure or efficacy in activating skeletal and cardiac RyRs.

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Single channel activity of the ryanodine receptor calcium release channel is modulated by FK‐506

Cited by 137 publications

References 31 publications

Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain

Interaction of FKBP12.6 with the Cardiac Ryanodine Receptor C-terminal Domain

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Functional implications of modifying RyR‐activating peptides for membrane permeability

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