Inactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide

doi:10.1016/S0143-4160(97)90072-5

Cell Calcium

Volume 22, Issue 6, December 1997, Pages 447-453

https://doi.org/10.1016/S0143-4160(97)90072-5 Get rights and content

Abstract

We have recently reported [Mészáros L.G., Minarovic I., Zahradníková A. Inhibition of the skeletal muscle ryanodine receptor calcium release channel by nitric oxide. FEBS Lett 1996; 380: 49–52] that nitric oxide (NO) reduces the activity of the skeletal muscle ryanodine receptor Ca²⁺ release channel (RyRC), a principal component of the excitation-contraction coupling machinery in striated muscles. Since (i) as shown here, we have obtained evidence which indicates that the NO synthase (eNOS) of cardiac muscle origin co-purified with RyRC-containing sarcoplasmic reticulum (SR) fractions; and (ii) the effects of NO donors on the release channel, as well as on cardiac function, appear somewhat contradictory, we have made an attempt to investigate the response of the cardiac RyRC to NO that is generated in situ from L-arginine in the NOS reaction. We found that L-arginine-derived NO inactivates Ca²⁺ release from cardiac SR and reduces the steady-state activity (i.e. open probability) of single RyRCs fused into a planar lipid bilayer. This reduction was prevented by NOS inhibitors and the NO quencher hemoglobin and was reversed by 2-mercaptoethanol. We thus conclude that: (i) in isolated SR preparations, it is possible to assess the effects of NO that is generated from L-arginine in the NOS reaction; and (ii) cardiac RyRc responds to NO in a manner which is identical to that we have previously found with the skeletal channel. These findings suggest that the direct modulation of the RyRC by NO is a signaling mechanism which likely participates in earlier demonstrated NO-induced myocardial contractility changes.

References (24)

J.L. Balligand et al.
Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes
J Biol Chem
(1995)
O. Feron et al.
Endothelial nitric oxide synthase targeting to caveolae
J Biol Chem
(1996)
H.H.W. Schmidt et al.
The nitric oxide and cGMP signal transduction system: regulation and mechanism of action
Biochim Biophys Acta
(1993)
R.C. Venema et al.
Role of the enzyme calmodulin-binding domain in membrane association and phospholipid inhibition of endothelial nitric oxide synthase
J Biol Chem
(1995)
R. Horn
Estimating the number of channels in patch recordings
Biophys J
(1991)
D. Stoyanovsky et al.
Nitric oxide activates skeletal and cardiac ryanodine receptors
Cell Calcium
(1997)
B. Aghdasi et al.
Multiple classes of sulfhydryls modulate the skeletal muscle Ca release channel
J Biol Chem
(1997)
A.C. Zable et al.
Glutathione modulates ryanodine receptor from skeletal muscle sarcoplasmic reticulum. Evidence for redox regulation of the Ca²⁺ release mechanism
J Biol Chem
(1997)
S. Moncada et al.
Nitric oxide: physiology, pathophysiology and pharmacology
Pharmacol Rev
(1991)
C. Nathan
Nitric oxide as a secretory product of mammalian cells
FASEB J
(1992)

M.S. Finkel et al.

Negative inotropic effects of cytokines on the heart mediated by nitric oxide

Science

(1992)

A.J.B. Brady et al.

Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia

Am J Physiol

(1992)

Cited by (105)

Increased constitutive nitric oxide production by whole body periodic acceleration ameliorates alterations in cardiomyocytes associated with utrophin/dystrophin deficiency
2017, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
NO modulates cardiac function based on its rate of production and concentration, which are dictated by the interplay between its synthesis, diffusion, inactivation, and crosstalk among three NO synthase (NOS) isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) [21]. In healthy striated muscle, NO modulates glucose uptake, vascular perfusion, mitochondrial function, and excitation-contraction coupling regulating Ca2 + release and entry [22]. Under physiological conditions, striated muscle cells constitutively produce local and small (nM) amounts of NO synthesized by nNOS and eNOS, which release NO in a Ca2 +- and calmodulin-dependent manner [23].
Duchenne Muscular Dystrophy (DMD) cardiomyopathy is a progressive lethal disease caused by the lack of the dystrophin protein in the heart. The most widely used animal model of DMD is the dystrophin-deficient mdx mouse; however, these mice exhibit a mild dystrophic phenotype with heart failure only late in life. In contrast, mice deficient for both dystrophin and utrophin (mdx/utrn^−/−, or dKO) can be used to model severe DMD cardiomyopathy where pathophysiological indicators of heart failure are detectable by 8–10 weeks of age. Nitric oxide (NO) is an important signaling molecule involved in vital functions of regulating rhythm, contractility, and microcirculation of the heart, and constitutive NO production affects the function of proteins involved in excitation-contraction coupling. In this study, we explored the efficacy of enhancing NO production as a therapeutic strategy for treating DMD cardiomyopathy using the dKO mouse model of DMD. Specifically, NO production was induced via whole body periodic acceleration (pGz), a novel non-pharmacologic intervention which enhances NO synthase (NOS) activity through sinusoidal motion of the body in a headward-footward direction, introducing pulsatile shear stress to the vascular endothelium and cardiomyocyte plasma membrane. Male dKO mice were randomized at 8 weeks of age to receive daily pGz (480 cpm, Gz ± 3.0 m/s², 1 h/d) for 4 weeks or no treatment, and a separate age-matched group of WT animals (pGz-treated and untreated) served as non-diseased controls. At the conclusion of the protocol, cardiomyocytes from untreated dKO animals had, respectively, 4.3-fold and 3.5-fold higher diastolic resting concentration of Ca^2 + ([Ca^2 +]_d) and Na⁺ ([Na⁺]_d) compared to WT, while pGz treatment significantly reduced these levels. For dKO cardiomyocytes, pGz treatment also improved the depressed contractile function, decreased oxidative stress, blunted the elevation in calpain activity, and mitigated the abnormal increase in [Ca^2 +]_d upon mechanical stress. These improvements culminated in a significant reduction in circulating cardiac troponin T (cTnT) and an extension of the median lifespan of dKO mice from 16 to 31 weeks. Treatment with L-NAME (NOS inhibitor) significantly decreased overall lifespan and abolished the cardioprotective properties elicited by pGz. Our results provide evidence that enhancement of NO synthesis by pGz can ameliorate cellular dysfunction in dKO cardiomyocytes and may represent a novel therapeutic intervention in DMD cardiomyopathy patients.
Regulation of ryanodine receptor ion channels through posttranslational modifications
2010, Current Topics in Membranes
Citation Excerpt :
Both RyR1 (Eu et al., 2000) and RyR2 (Xu et al., 1998) are endogenously S-nitrosylated, suggesting that NO is a physiological modulator of skeletal and cardiac muscle excitation–contraction coupling. In in vitro studies, NO or NO-related species activated or inhibited RyRs depending on donor concentration, membrane potential, the presence of channel agonists, and other sulfhydryl modifying reagents (Aghdasi, Reid, & Hamilton, 1997; Hart & Dulhunty, 2000; Meszaros, Minarovic, & Zahradnikova, 1996; Suko, Drobny, & Hellmann, 1999; Zahradnikova, Minarovic, Venema, & Meszaros, 1997). Low physiological concentrations of NO S-nitrosylated and activated RyR1 at tissue pO2 (~ 10 mmHg) but not in ambient air (pO2 ~ 150 mmHg) (Eu et al., 2000).
The ryanodine receptors (RyRs) are cation-selective channels that release Ca²⁺ from an intracellular Ca²⁺ storing compartment, the endo/sarcoplasmic reticulum, during an action potential in a process known as “excitation–contraction (E–C) coupling.” The released Ca²⁺ ions regulate a wide variety of biological functions. This chapter focuses on the regulation of the skeletal muscle and cardiac muscle RyRs by protein kinases and redox active species. The RyRsare 2200 kDa Ca²⁺-gated ion channels that are regulated, in addition to Ca²⁺ and endogenous effectors such as Mg²⁺ and ATP, by cAMP-dependent protein kinase A, calmodulin-dependent kinase II, protein kinase C, and protein phosphatases 1 and 2A. Thiols that serve as targets for reactive oxygen and nitrogen molecules determine the redox state and modulate the activity of the RyRs. There are three mammalian RyR isoforms. RyR1 is found in the sarcoplasmic reticulum (SR) membrane of skeletal muscle, while RyR2 is present in heart muscle. In mammalian cells, RyR3 is coexpressed with one or two of the other RyR isoforms at low levels. All three isoforms are present in smooth muscle and brain. The third mammalian RyR isoform, RyR3, contains putative phosphorylation and redox active sites; however, coexpression with the other mammalian RyR isoforms has hindered establishment of a specific cellular role.
Cardiomyocyte depolarization triggers NOS-dependent NO transient after calcium release, reducing the subsequent calcium transient
2021, Basic Research in Cardiology
Cardioprotective Effect of Whole Body Periodic Acceleration in Dystrophic Phenotype mdx Rodent
2021, Frontiers in Physiology
Examination of the changes in calcium homeostasis in the delayed antiarrhythmic effect of sodium nitrite
2019, International Journal of Molecular Sciences
Effects of S-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback
2018, Cardiovascular Toxicology

View all citing articles on Scopus

^∗: Dr Igor Minarovic is on leave from the Institute of Molecular Physiology and Genetics, Slovak Academy of Science, Bratislava, Slovak Republic

View full text

ResearchInactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide

Abstract

J Biol Chem

J Biol Chem

Biochim Biophys Acta

J Biol Chem

Biophys J

Cell Calcium

J Biol Chem

J Biol Chem

Nitric oxide: physiology, pathophysiology and pharmacology

Pharmacol Rev

Nitric oxide as a secretory product of mammalian cells

FASEB J

Negative inotropic effects of cytokines on the heart mediated by nitric oxide

Science

Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia

Am J Physiol

Research
Inactivation of the cardiac ryanodine receptor calcium release channel by nitric oxide