Functional implications of modifying RyR‐activating peptides for membrane permeability

Dulhunty, Angela F.; Cengia, Louise; Young, J E; Pace, Suzy M.; Harvey, Peta J.; Lamb, Graham D.; Chan, Yiu-Ngok; Wimmer, Norbert; Tóth, István

doi:10.1038/sj.bjp.0705981

Cited by 16 publications

(13 citation statements)

References 36 publications

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“…Lipidation of ryanodine receptor agonist [D-Arg 18 ]peptide A2 (Fig. 10b) with LAA maintained peptides' α-helical structures, increased peptides' Ca 2+ release activities and permeabilities across the Caco-2 cell monolayers as compared to that of the native peptide [62]. LAA conjugations enhanced the serum stability of thymopentin TP5 (RKDVY, Fig.…”

Section: Lipoamino Acids (Laas)mentioning

confidence: 95%

Converting Peptides into Drug Leads by Lipidation

Zhang¹,

Bułaj²

2012

CMC

171

139

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Ulceration in the gastrointestinal (GI) mucosa is a common disorder in humans. It has been shown that cigarette smoking is closely related to the increase of peptic ulcer and also plays an inhibitory role on ulcer healing. However, the underlying mechanisms by which cigarette smoke exerts these adverse effects remain largely unknown. It is perhaps partly due to the complexity of chemical compositions in the smoke and furthermore their pathological actions are largely undefined. In this review, we have highlighted the potential adverse effects of the toxic chemical components in cigarette smoke and summarized their possible mechanisms of actions on ulcer formation and healing in the GI tract. We also discuss in detail how cigarette smoke disturbs cell proliferation, influences mucus synthesis and secretion, delays blood vessel formation, and interferes the innate immune responses during ulceration and repair in the GI mucosa.

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Section: Lipoamino Acids (Laas)mentioning

confidence: 95%

Converting Peptides into Drug Leads by Lipidation

Zhang¹,

Bułaj²

2012

CMC

171

139

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“…So far, we have shown that attaching lipid tails to the A peptides shown in Fig. 8 substantially increases the membrane permeability of the compounds and, in fact, enhances their interactions with RyRs, 80 but the modified peptides have a deleterious effect on membrane potential. We are now using a different approach with synthetic compounds that mimic peptide structure.…”

Section: An Explosion Of Information Between 1990 and 2005mentioning

confidence: 94%

EXCITATION–CONTRACTION COUPLING FROM THE 1950s INTO THE NEW MILLENNIUM

Dulhunty

2006

Clin Exp Pharma Physio

131

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SUMMARY1. Excitation-contraction coupling is broadly defined as the process linking the action potential to contraction in striated muscle or, more narrowly, as the process coupling surface membrane depolarization to Ca 2+ release from the sarcoplasmic reticulum.2. We now know that excitation-contraction coupling depends on a macromolecular protein complex or 'calcium release unit'. The complex extends the extracellular space within the transverse tubule invaginations of the surface membrane, across the transverse tubule membrane into the cytoplasm and then across the sarcoplasmic reticulum membrane and into the lumen of the sarcoplasmic reticulum.3. The central element of the macromolecular complex is the ryanodine receptor calcium release channel in the sarcoplasmic reticulum membrane. The ryanodine receptor has recruited a surface membrane L-type calcium channel as a 'voltage sensor' to detect the action potential and the calcium-binding protein calsequestrin to detect in the environment within the sarcoplasmic reticulum. Consequently, the calcium release channel is able to respond to surface depolarization in a manner that depends on the Ca 2+ load within the calcium store.4. The molecular components of the 'calcium release unit' are the same in skeletal and cardiac muscle. However, the mechanism of excitation-contraction coupling is different. The signal from the voltage sensor to ryanodine receptor is chemical in the heart, depending on an influx of external Ca 2+ through the surface calcium channel. In contrast, conformational coupling links the voltage sensor and the ryanodine receptor in skeletal muscle. 5. Our current understanding of this amazingly efficient molecular signal transduction machine has evolved over the past 50 years. None of the proteins had been identified in the 1950s; indeed, there was debate about whether the molecules involved were, in fact, protein. Nevertheless, a multitude of questions about the molecular interactions and structures of the proteins and their interaction sites remain to be answered and provide a challenge for the next 50 years.

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“…An attractive and feasible route for the pharmacological modulation of RyR2 may include the use of recombinant proteins or small synthetic peptides that target specific functional epitopes within RyR2 to stabilise the channel [18,74,75,122]. Since this approach confers sequence-specific interaction, and thus can be tailored to numerous intra-RyR2 targets, it offers the potential ability to modulate discrete aspects of RyR2 function.…”

Section: Ryr2-targeted Anti-arrhythmic Therapies a Pharmacological Mmentioning

confidence: 99%

Developing New Anti-Arrhythmics: Clues from the Molecular Basis of Cardiac Ryanodine Receptor (RyR2) Ca2+-Release Channel Dysfunction

George¹,

Lai²

2007

CPD

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Sudden cardiac death (SCD) remains a major cause of mortality, and despite our knowledge of the causative genetic, molecular and biochemical cellular mechanisms involved, effective therapeutic strategies are lacking. Perturbations in cardiac Ca2+ handling promote arrhythmias and there is enormous interest in developing new anti-arrhythmics aimed at correcting Ca2+ release dysfunction. In particular, abnormal Ca2+ release arising as a result of acquired or genetic defects in cardiac ryanodine receptors (RyR2) has emerged as an important arrhythmogenic trigger in heart failure, and in a devastating genetic arrhythmia syndrome termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we evaluate how experimental insights into RyR2 structure-function are unravelling the precise molecular basis of channel dysfunction and are advancing the development of new therapeutic strategies. We also discuss the functional role of RyR2 in the context of the exquisite synergism existing between numerous cellular components involved in cardiac Ca2+ signalling, and how these complex interactions may be used to design new anti-arrhythmic approaches that target multiple facets of RyR2 regulation.

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Functional implications of modifying RyR‐activating peptides for membrane permeability

Cited by 16 publications

References 36 publications

Converting Peptides into Drug Leads by Lipidation

Converting Peptides into Drug Leads by Lipidation

EXCITATION–CONTRACTION COUPLING FROM THE 1950s INTO THE NEW MILLENNIUM

Developing New Anti-Arrhythmics: Clues from the Molecular Basis of Cardiac Ryanodine Receptor (RyR2) Ca2+-Release Channel Dysfunction

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