Carnosine is a novel peptide modulator of intracellular calcium and contractility in cardiac cells

Myocardial contractile failure is a common cause of morbidity and mortality in patients with ischemic heart disease and systemic inflammatory states such as sepsis. Accumulating evidence indicates that contractile failure is associated with dysregulation of myoplasmic calcium levels. In a search for biochemical causes for contractile dysfunction, we found that the dipeptide carnosine improves cardiac contractility and tested the possibility that carnosine plays a role in the regulation of intracellular calcium. Carnosine increased contractility in a dose-dependent manner (1-10 mM) in isolated perfused rat hearts. and it also increased free intracellular calcium levels in isolated myocytes. Carnosine increased myocyte tension via calcium release from the ryanodine receptor calcium release channel in skinned myocardial fibers and increased open-state probability and dwell time of the isolated ryanodine receptor calcium release channel in lipid bilayers. In addition. we report that carnosine sensitizes the contractile proteins so calcium. These results suggest a novel role for carnosine as a modulator of intracellular calcium and contractility in cardiac tissue.

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H2O2 and ethanol act synergistically to gate ryanodine receptor/calcium-release channel

AJP Cell Physiology ◽

10.1152/ajpcell.2000.279.5.c1366 ◽

2000 ◽

Vol 279 (5) ◽

pp. C1366-C1374 ◽

Cited By ~ 21

Author(s):

Toshiharu Oba ◽

Tatsuya Ishikawa ◽

Takashi Murayama ◽

Yasuo Ogawa ◽

Mamoru Yamaguchi

Keyword(s):

Skeletal Muscle ◽

Lipid Bilayers ◽

Ryanodine Receptor ◽

Calcium Release ◽

Physiological Role ◽

Channel Activity ◽

Calcium Release Channel ◽

Open Probability ◽

Skeletal Muscle Function ◽

Release Channel

We examined the effect of low concentrations of H2O2 on the Ca2+-release channel/ryanodine receptor (RyR) to determine if H2O2 plays a physiological role in skeletal muscle function. Sarcoplasmic reticulum vesicles from frog skeletal muscle and type 1 RyRs (RyR1) purified from rabbit skeletal muscle were incorporated into lipid bilayers. Channel activity of the frog RyR was not affected by application of 4.4 mM (0.02%) ethanol. Open probability ( P o) of such ethanol-treated RyR channels was markedly increased on subsequent addition of 10 μM H2O2. Increase of H2O2to 100 μM caused a further increase in channel activity. Application of 4.4 mM ethanol to 10 μM H2O2-treated RyRs activated channel activity. Exposure to 10 or 100 μM H2O2 alone, however, failed to increase P o. Synergistic action of ethanol and H2O2 was also observed on the purified RyR1 channel, which was free from FK506 binding protein (FKBP12). H2O2 at 100–500 μM had no effect on purified channel activity. Application of FKBP12 to the purified RyR1 drastically decreased channel activity but did not alter the effects of ethanol and H2O2. These results suggest that H2O2 may play a pathophysiological, but probably not a physiological, role by directly acting on skeletal muscle RyRs in the presence of ethanol.

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Reversible Block of the Calcium Release Channel/Ryanodine Receptor by Protamine, a Heparin Antidote

Molecular Biology of the Cell ◽

10.1091/mbc.11.7.2213 ◽

2000 ◽

Vol 11 (7) ◽

pp. 2213-2219 ◽

Cited By ~ 16

Author(s):

Peter Koulen ◽

Barbara E. Ehrlich

Keyword(s):

Lipid Bilayers ◽

Ryanodine Receptor ◽

Calcium Release ◽

Single Channel ◽

Reversible Inhibitor ◽

Channel Activity ◽

Calcium Release Channel ◽

Release Channel ◽

Mouse Muscle ◽

Cytoplasmic Side

Channel activity of the calcium release channel from skeletal muscle, ryanodine receptor type 1, was measured in the presence and absence of protamine sulfate on the cytoplasmic side of the channel. Single-channel activity was measured after incorporating channels into planar lipid bilayers. Optimally and suboptimally calcium-activated calcium release channels were inactivated by the application of protamine to the cytoplasmic side of the channel. Recovery of channel activity was not observed while protamine was present. The addition of protamine bound to agarose beads did not change channel activity, implying that the mechanism of action involves an interaction with the ryanodine receptor rather than changes in the bulk calcium concentration of the medium. The block of channel activity by protamine could be reversed either by removal by perfusion with buffer or by the addition of heparin to the cytoplasmic side of the channel. Microinjection of protamine into differentiated C2C12 mouse muscle cells prevented caffeine-induced intracellular calcium release. The results suggest that protamine acts on the ryanodine receptor in a similar but opposite manner from heparin and that protamine can be used as a potent, reversible inhibitor of ryanodine receptor activity.

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330 Calcium sensitivity characteristics of the cardiac intracellular calcium release channel (ryanodine receptor) following chronic exposure to excessive circulating catecholamines

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(03)90190-1 ◽

2003 ◽

Vol 2 (1) ◽

pp. 62

Author(s):

M SCOOTE ◽

S HARDING ◽

K MACLEOD ◽

A WILLIAMS

Keyword(s):

Intracellular Calcium ◽

Ryanodine Receptor ◽

Chronic Exposure ◽

Calcium Release ◽

Calcium Sensitivity ◽

Calcium Release Channel ◽

Release Channel ◽

Intracellular Calcium Release

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“Ryanopathies” and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?

Cell Death and Disease ◽

10.1038/s41419-021-04337-9 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Yvonne Sleiman ◽

Alain Lacampagne ◽

Albano C. Meli

Keyword(s):

Intracellular Calcium ◽

Ryanodine Receptor ◽

Calcium Release ◽

Current Knowledge ◽

Cell Types ◽

Calcium Release Channel ◽

Release Channel ◽

Cellular Environment ◽

Intracellular Ca

AbstractThe regulation of intracellular calcium (Ca2+) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients’ cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient’s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.

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