Arg615Cys Substitution in Pig Skeletal Ryanodine Receptors Increases Activation of Single Channels by a Segment of the Skeletal DHPR II-III Loop

Gallant, Esther M.; Curtis, Suzanne M.; Pace, Suzy M.; Dulhunty, Angela F.

doi:10.1016/s0006-3495(01)76147-4

Cited by 15 publications

(18 citation statements)

References 41 publications

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“…The greater increase in relative mean current at j40 mV ( Figure 5B) was due to the fact that the closed times were longer, and the frequency of events lower, in control activity at that potential than control activity at k40 mV. The effects of peptide A1(-R18) on single-channel parameters (a strong decrease in closed times and an increase in event frequency, with only a small increase in mean open time) were the same as the effects seen with peptide A1 [2,23]. The major difference between the peptides was in the magnitude of the effects, which was 2-10-fold greater with A1(-R18) than with A1.…”

Section: Enhanced A1(d-r18)-induced Activation Of Single Ryr Channelsmentioning

confidence: 73%

The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment

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Pace

Curtis

et al. 2003

Biochemical Journal

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An alpha-helical II-III loop segment of the dihydropyridine receptor activates the ryanodine receptor calcium-release channel. We describe a novel manipulation in which this agonist's activity is increased by modifying its surface structure to resemble that of a toxin molecule. In a unique system, native beta-sheet scorpion toxins have been reported to activate skeletal muscle ryanodine receptor calcium channels with high affinity by binding to the same site as the lower-affinity alpha-helical dihydropyridine receptor segment. We increased the alignment of basic residues in the alpha-helical peptide to mimic the spatial orientation of active residues in the scorpion toxin, with a consequent 2-20-fold increase in the activity of the alpha-helical peptide. We hypothesized that, like the native peptide, the modified peptide and the scorpion toxin may bind to a common site. This was supported by (i) similar changes in ryanodine receptor channel gating induced by the native or modified alpha-helical peptide and the beta-sheet toxin, a 10-100-fold reduction in channel closed time, with a < or = 2-fold increase in open dwell time and (ii) a failure of the toxin to further activate channels activated by the peptides. These results suggest that diverse structural scaffolds can present similar conformational surface properties to target common receptor sites.

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Section: Enhanced A1(d-r18)-induced Activation Of Single Ryr Channelsmentioning

confidence: 73%

The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment

Green

Pace

Curtis

et al. 2003

Biochemical Journal

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“…Ribba et al [25] showed that the Arg552Cys mutation in the von Willebrand factor resulted in abnormal folding and loss of function resulting in type 2A-like phenotype of von Willebrand disease. The Arg615Cys substitution in ryanodine receptors increases calcium release in malignant hyperthermia-susceptible pigs [9].…”

Section: Discussionmentioning

confidence: 99%

Association of a missense mutation in the bovine leptin gene with carcass fat content and leptin mRNA levels

et al. 2002

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-Previously, we have shown that alleles of the BM1500 microsatellite, located 3.6 kb downstream of the leptin gene in cattle, were associated with carcass fat measures in a population of 154 unrelated beef bulls. Subsequently, a cytosine (C) to thymine (T) transition that encoded an amino acid change of an arginine to a cysteine was identified in exon 2 of the leptin gene. A PCR-RFLP was designed and allele frequencies in four beef breeds were correlated with levels of carcass fat. The T allele was associated with fatter carcasses and the C allele with leaner carcasses. The frequencies of the SNP alleles among breeds indicated that British breeds have a higher frequency of the T allele whereas the continental breeds have a higher occurrence of the C allele. A ribonuclease protection assay was developed to quantify leptin mRNA in a separate group of animals selected by genotype. Animals homozygous for thymine expressed higher levels of leptin mRNA. This may suggest that the T allele, which adds an extra cysteine to the protein, imparts a partial loss of biological function and hence could be the causative mutation.leptin / cattle / obese / fat / marbling

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“…First, it increases transient activity in skeletal RyRs with high affinity (Ն10 nM) and releases Ca 2ϩ from skeletal SR (5,6,10,(12)(13)(14)(15)(16)(17)(18). Ca 2ϩ -induced Ca 2ϩ release from cardiac SR is enhanced by the peptide and cardiac RyRs activated at sub-activating cis [Ca 2ϩ ].…”

Section: Discussionmentioning

confidence: 99%

“…3 The second action is a voltage-independent inhibition, seen specifically with the modified A1-R18D at Ն10 nM in skeletal and cardiac RyRs with 100 M cis Ca 2ϩ . 3 The native peptide A is less active with 100 M cis Ca 2ϩ than with lower [Ca 2ϩ ] (12,17). Because peptide structure is not Ca 2ϩ -dependent, 3 this inhibition raises the possibility either that there is a separate inhibitory site or the activation site can become inhibitory.…”

Section: Discussionmentioning

confidence: 99%

“…A second region of the II-III loop, the A region (residues 671-690), is of interest because its corresponding peptide fragment induces Ca 2ϩ release from the SR and enhances current flow through RyR channels with high affinity (5,6,10,(12)(13)(14)(15)(16)(17)(18). Although the A region is not essential for skeletal EC coupling in myocytes (7,9), it may play a role in the DHPR-RyR interaction (8), and it is a useful probe for assessing RyR function (11,17,19).…”

Section: Excitation-contraction (Ec)mentioning

confidence: 99%

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Multiple Actions of Imperatoxin A on Ryanodine Receptors

Dulhunty¹,

Curtis²,

Watson³

et al. 2004

Journal of Biological Chemistry

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Imperatoxin A is a high affinity activator of ryanodine receptors. The toxin contains a positively charged surface structure similar to that of the A fragment of skeletal dihydropyridine receptors (peptide A), suggesting that the toxin and peptide could bind to a common site on the ryanodine receptor. However, the question of a common binding site has not been resolved, and the concentration dependence of the actions of the toxin has not been fully explored. We characterize two novel high affinity actions of the toxin on the transient gating of cardiac and skeletal channels, in addition to the well documented lower affinity induction of prolonged substates. Transient activity was (a) enhanced with 0.2-10 nM toxin and (b) depressed by >50 nM toxin. The toxin at >1 nM enhanced Ca 2؉ release from SR in a manner consistent with two independent activation processes. The effects of the toxin on transient activity, as well as the toxin-induced substate, were independent of cytoplasmic Ca 2؉ or Mg 2؉ concentrations or the presence of adenine nucleotide and were seen in diisothiocyanostilbene-2,2-disulfonic acid-modified channels. Peptide A activated skeletal and cardiac channels with 100 nM cytoplasmic Ca 2؉ and competed with Imperatoxin A in the high affinity enhancement of transient channel activity and Ca 2؉ release from SR. In contrast to transient activity, prolonged substate openings induced by the toxin were not altered in the presence of peptide A. The results suggest that Imperatoxin A has three independent actions on ryanodine receptor channels and competes with peptide A for at least one action. Excitation-contraction (EC)1 coupling is the process that facilitates Ca 2ϩ release from the sarcoplasmic reticulum (SR) of muscle fibers following depolarization of the surface/transverse (t-) tubule membrane. A protein-protein interaction between the dihydropyridine receptor (DHPR) and ryanodine receptor (RyR) underlies EC coupling in skeletal muscle. The DHPR L-type Ca 2ϩ channel in the t-tubule membrane detects surface depolarization and transmits a signal to the RyR channel in the SR via an interaction between the cytoplasmic domains of the two proteins. The interacting region of the DHPR is located between the second and third transmembrane repeats in the ␣1

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Arg615Cys Substitution in Pig Skeletal Ryanodine Receptors Increases Activation of Single Channels by a Segment of the Skeletal DHPR II-III Loop

Cited by 15 publications

References 41 publications

The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment

The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment

Association of a missense mutation in the bovine leptin gene with carcass fat content and leptin mRNA levels

Multiple Actions of Imperatoxin A on Ryanodine Receptors

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