Activating the ryanodine receptor with dihydropyridine receptor II-III loop segments: size and charge do matter

Green, Daniel; Pace, Suzy M.; Young, Jaqui; Dulhunty, Angela F.

doi:10.2741/1443

Cited by 8 publications

(8 citation statements)

References 31 publications

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“…7). 45,72–74 The results show, reassuringly, that the structures of 20 residue peptides are the same as the structures of corresponding regions in the full II–III loop. However, the only highly structured region of the loop is the A region, which, although it interacts with the RyR, has not been found to be major player in EC coupling.…”

Section: An Explosion Of Information Between 1990 and 2005mentioning

confidence: 65%

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

Dulhunty

2006

Clin Exp Pharma Physio

135

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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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Section: An Explosion Of Information Between 1990 and 2005mentioning

confidence: 65%

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

Dulhunty

2006

Clin Exp Pharma Physio

135

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“…This is not surprising given the frequency of charged amino acids near the ends of C S and in additional amino acids in 720 Leu-Glu 765 . In a parallel situation, a significant loss of activity is seen when the predominantly positively charged peptide A S ( 671 Thr-Leu 690 ) is modified by the addition of residues 691-710, which contain several negative charges [40].…”

Section: Different Peptide Mechanisms Are Revealed By Different Expermentioning

confidence: 99%

Regulation of skeletal ryanodine receptors by dihydropyridine receptor II–III loop C-region peptides: relief of Mg2+ inhibition

Haarmann

Dulhunty²,

Laver

2005

Biochemical Journal

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The aim of the present study was to explore interactions between surface-membrane DHPR (dihydropyridine receptor) Ca 2+ channels and RyR (ryanodine receptor) Ca 2+ channels in skeletalmuscle sarcoplasmic reticulum. The C region ( 725 Phe-Pro 742 ) of the linker between the 2nd and 3rd repeats (II-III loop) of the α 1 subunit of skeletal DHPRs is essential for skeletal excitationcontraction coupling, which requires a physical interaction between the DHPR and RyR and is independent of external Ca 2+ . Little is known about the regulatory processes that might take place when the two Ca 2+ channels interact. Indeed, interactions between C fragments of the DHPR (C peptides) and RyR have different reported effects on Ca 2+ release from the sarcoplasmic reticulum and on RyR channels in lipid bilayers. To gain insight into functional interactions between the proteins and to explore different reported effects, we examined the actions of C peptides on RyR1 channels in lipid bilayers with three key RyR regulators, Ca 2+ , Mg 2+ and ATP. We identified four discrete actions: two novel, low-affinity (> 10 µM), rapidly reversible effects (fast inhibition and decreased sensitivity to Mg 2+ inhibition) and two slowly reversible effects (high-affinity activation and a slow-onset, low-affinity inhibition). Fast inhibition and high-affinity activation were decreased by ATP. Therefore peptide activation in the presence of ATP and Mg 2+ , used with Ca 2+ release assays, depends on a mechanism different from that seen when Ca 2+ is the sole agonist. The relief of Mg 2+ inhibition was particularly important since RyR activation during excitation-contraction coupling depends on a similar decrease in Mg 2+ inhibition.

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“…A 20‐residue peptide corresponding to a sequence in the loop ( A peptide) is active on skeletal and cardiac RyRs . We have used NMR techniques to determine the structural requirements for critical residues to either activate or inhibit RyRs …”

Section: Introductionmentioning

confidence: 99%

Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels

2018

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Ryanodine receptor (RyR) Ca -release channels are essential for contraction in skeletal and cardiac muscle and are prime targets for modification of contraction in disorders that affect either the skeletal or heart musculature. We designed and synthesized a number of compounds with structures based on a naturally occurring peptide (A peptides) that modifies the activity of RyRs. In total, 34 compounds belonging to eight different classes were prepared. The compounds were screened for their ability to enhance Ca release from isolated cardiac sarcoplasmic reticulum (SR) vesicles, with 25 displaying enhanced Ca release. Competition studies with the parent peptides indicated that the synthetic compounds act at a competing site. The activity of the most effective of the compounds, BIT 180, was further explored using Ca release from skeletal SR vesicles and contraction in intact skeletal muscle fibers. The compounds did not alter tension in intact fibers, indicating that (as expected) they are not membrane permeable, but importantly, that they are not toxic to the intact cells. Proof in principal that the compounds would be effective in intact muscle fibers if rendered membrane permeable was obtained with a structurally related membrane-permeable scorpion toxin (imperatoxin A), which was found to enhance contraction.

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Activating the ryanodine receptor with dihydropyridine receptor II-III loop segments: size and charge do matter

Cited by 8 publications

References 31 publications

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

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

Regulation of skeletal ryanodine receptors by dihydropyridine receptor II–III loop C-region peptides: relief of Mg2+ inhibition

Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels

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