The Skeletal Muscle Calcium Release Channel

Eu, Jerry P.; Sun, Junhui; Xu, Le; Stamler, Jonathan S.; Meissner, Gerhard

doi:10.1016/s0092-8674(00)00054-4

Cited by 394 publications

(164 citation statements)

References 55 publications

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“…For example, NO augments the RyR activity by protein nitrosylation in a reversible manner capable of optimizing SR activity throughout the cardiac cycle (32). NO may additionally influence SERCA activity, although this remains controversial with studies demonstrating opposite results (16,33). Excessive NO, however, (even under low O 2…”

Section: Discussionmentioning

confidence: 99%

“…Experiments were then repeated with the addition of allopurinol (10 Ϫ4 M, DSM Pharmaceuticals, Greenville, NC) at a concentration where selective XOR inhibition occurs. All experiments were conducted at 37°C and in room air (PO 2 Ϸ 20%); increased O 2 concentrations are known to disrupt NO signaling particularly its influence over the ryanodine receptor (RYR) (16).…”

Section: Immunoprecipitation and Western Blotsmentioning

confidence: 99%

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Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling

Khan

Lee

Minhas

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

212

206

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Although interactions between superoxide (O 2•؊ ) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide O 2•؊ -producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated O 2•؊ production, which in turn depresses myocardial excitation-contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an O 2•؊ -generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role.

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Section: Discussionmentioning

confidence: 99%

Section: Immunoprecipitation and Western Blotsmentioning

confidence: 99%

Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling

Khan

Lee

Minhas

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

212

206

View full text Add to dashboard Cite

show abstract

“…The ratio of superoxide͞NO production by NOS is an important determinant of the redox milieu. It is established that both skeletal (32), and cardiac (31) RYRs are, in fact, activated by S-nitrosylation (33). The cardiac ryanodine isoform, which is S-nitrosylated under basal conditions, has been shown to colocalize with NOS1 in the SR (24,34).…”

Section: Discussionmentioning

confidence: 99%

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Steppan

Ryoo

Schuleri

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac myocytes contain two constitutive NO synthase (NOS) isoforms with distinct spatial locations, which allows for isoformspecific regulation. One regulatory mechanism for NOS is substrate (L-arginine) bioavailability. We tested the hypothesis that arginase (Arg), which metabolizes L-arginine, constrains NOS activity in the cardiac myocyte in an isoform-specific manner. Arg activity was detected in both rat heart homogenates and isolated myocytes. Although both Arg I and II mRNA and protein were present in whole heart, Arg II alone was found in isolated myocytes. Arg inhibition with S-(2-boronoethyl)-L-cysteine (BEC) augmented Ca 2؉ -dependent NOS activity and NO production in myocytes, which did not depend on extracellular L-arginine. Arg II coimmunoprecipited with NOS1 but not NOS3. Isolation of myocyte mitochondrial fractions in combination with immuno-electron microscopy demonstrates that Arg II is confined primarily to the mitochondria. Because NOS1 positively modulates myocardial contractility, we determined whether Arg inhibition would increase basal myocardial contractility. Consistent with our hypothesis, Arg inhibition increased basal contractility in isolated myocytes by a NOS-dependent mechanism. Both the Arg inhibitors N-hydroxynor-L-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N G -nitro-L-arginine methyl ester and S-methyl-L-thiocitrulline, respectively. Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice. We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain. These findings have implications for therapy in pathophysiologic states such as aging and heart failure in which myocardial NO signaling is disrupted. mitochondria ͉ L-arginine pools ͉ spatial confinement

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“…Furthermore, disruption of this signaling is involved in the development of cardiac pathologies such as congestive heart failure. Other research has also elucidated a key role for nNOSgenerated NO in controlling cardiac contractility through altered intracellular calcium storage (7), potentially through the formation of SNO on the ryanodine receptor (RyR) (8). Through the elegant use of knockout mice, Khan et al (4) have connected these observations, thereby demonstrating that the regulation of XOR-generated superoxide represents another site of NO modulation of cardiac contractility.…”

mentioning

confidence: 99%

“…For background, it is of value to briefly summarize the XOR system. XOR is widely distributed and is implicated in apoptosis and pathophysiology (8). In vivo, the system exists in two forms: xanthine dehydrogenase (XDH) and xanthine oxidase (XO).…”

mentioning

confidence: 99%