Elsevier

Biochemical Pharmacology

Volume 57, Issue 10, 15 May 1999, Pages 1079-1084
Biochemical Pharmacology

Commentaries
Regulation of ryanodine receptors by reactive nitrogen species

https://doi.org/10.1016/S0006-2952(98)00360-8Get rights and content

Abstract

The ryanodine receptors (RyRs) are large intracellular calcium release channels that play an important role in the control of the calcium levels in excitable and non-excitable cells. Many endogenous modulators such as Mg2+, ATP, or calmodulin can affect the channel activities of the three known mammalian RyR isoforms. RyRs also are known to be redox-responsive. However, the molecular basis and the physiological relevance of redox modulation of RyRs are unclear. Recent evidence suggests that nitric oxide (NO) and related molecules may be endogenous regulators of the skeletal and cardiac muscle RyRs. The two tissues express nitric oxide synthases (NOSs), and NO or NO-related species have been shown to affect Ca2+ release channel activities directly via covalent modifications of thiol groups. Both an oxidative and a nitrosative modification of RyRs have been described, leading to either a reversible or irreversible alteration of RyR ion channel activity. Additional mechanisms of regulation may include cyclic GMP-dependent signaling pathways and NO modification of RyR regulatory proteins such as the surface membrane L-type Ca2+ channel. Modification of RyRs by NO may influence a variety of physiological functions such as insulin release, vasomotor control, and muscle contraction.

Section snippets

RyRs

RyRs are calcium channels that control the levels of intracellular Ca2+ by releasing Ca2+ from intracellular calcium-storing organelles 6, 7, 8. They were named RyRs because of the specific binding of the plant alkaloid ryanodine, which has facilitated their purification and characterization. Mammalian tissues express three structurally and functionally related RyRs (RyR1, RyR2, and RyR3) that are encoded by three different genes. RyR1, RyR2, and RyR3 are also known as skeletal, cardiac, and

NOSs

NO is derived from one of the chemically equivalent guanidino nitrogens of l-arginine in a reaction catalyzed by one of three NOSs [19]. nNOS (NOS-1), first identified in neurons, and eNOS (NOS-3), first identified in endothelial cells, are most often constitutively expressed 2, 3. They are activated by extracellular signals that increase intracellular [Ca2+] and thereby facilitate the interaction of the two enzymes with calmodulin. More recent evidence suggests that they can be also activated

Localization of NOSs and RyRs in striated muscle

Regulation of RyRs by NO (or related molecules) does not require that NOS and RyR co-localize, nor must they be expressed in the same cell. After all, NO, initially identified as the endothelial derived relaxation factor, has been shown to diffuse from endothelial cells to vascular smooth muscle cells to cause vasorelaxation [27]. Nevertheless, a close proximity of the two proteins could be advantageous in that it should restrict NO signaling to specific targets within a limited

Regulation of RyR by NO via cGMP-dependent pathways

NO increases cGMP levels in muscle, and such increases may alter RyR activities 1, 2, 3. One possible mechanism may involve phosphorylation of RyRs by cGMP-dependent protein kinase [44]. cGMP also may indirectly control RyRs by changing the cytosolic levels of RyR effectors such as cADP-ribose. In sea urchin eggs, NO increased the levels of the RyR activator cADP-ribose via a cGMP-dependent mechanism [45]. Treatment of a pheochromocytoma cell line, PC12, with NO donors led to a modest increase

Regulation of L-type Ca2+ channels by NO

In striated muscle, RyRs are regulated by L-type Ca2+ channels via either a direct physical interaction (in skeletal muscle) or an influx of extracellular Ca2+ (in cardiac muscle) 6, 7, 8. NO therefore also may modulate the release of Ca2+ from the SR by interacting with L-type Ca2+ channels via cGMP-dependent and independent pathways. Wang et al.[26] have suggested a cGMP-mediated regulation of L-type Ca2+ channels in cat atrial myocytes. Campbell et al.[24] studied the effects of NO-related

Concluding remarks

Although recent progress has led to an improved understanding of the interaction of NO and related species with RyRs, several major questions regarding their action on SR Ca2+ release remain to be resolved:

  • 1.

    Is NO a direct physiological modulator of RyRs in striated muscle? The cardiac RyR is endogenously S-nitrosylated [18]; however, the extent of S-nitrosylation was low and the physiological significance of this reaction (inhibitory or stimulatory) remains to be better established.

  • 2.

    Do RyRs and

Acknowledgements

Support by United States Public Health Service Grants HL52529 and HL59130 (to J.J.S.) and AR18687 and HL27430 (to G.M.) is gratefully acknowledged.

References (62)

  • U. Frandsen et al.

    Localization of nitric oxide synthase in human skeletal muscle

    Biochem Biophys Res Commun

    (1996)
  • J.E. Brenman et al.

    Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains

    Cell

    (1996)
  • V.J. Venema et al.

    Communication-interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle

    J Biol Chem

    (1997)
  • J. Couet et al.

    Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins

    J Biol Chem

    (1997)
  • L. Kobzik et al.

    Endothelial type nitric oxide synthase in skeletal muscle fibers: Mitochondrial relationships

    Biochem Biophys Res Commun

    (1995)
  • 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)
  • N.J. Willmott et al.

    Nitric oxide induces intracellular Ca2+ mobilization and increases secretion of incorporated 5-hydroxytryptamine in rat pancreatic cells

    FEBS Lett

    (1995)
  • J. Suko et al.

    Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase

    Biochim Biophys Acta

    (1993)
  • N. Willmott et al.

    Nitric oxide-induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway

    J Biol Chem

    (1996)
  • E. Clementi et al.

    The type 2 ryanodine receptor of neurosecretory PC12 cells is activated by cyclic ADP-ribose

    J Biol Chem

    (1996)
  • G. Liu et al.

    Molecular interaction between ryanodine receptor and glycoprotein triadin involves redox cycling of functionally important hyperreactive sulfhydryls

    J Biol Chem

    (1994)
  • T.G. Favero et al.

    Hydrogen peroxide stimulates the Ca2+ release channel from skeletal muscle sarcoplasmic reticulum

    J Biol Chem

    (1995)
  • J.J. Marengo et al.

    Sulfhydryl oxidation modifies the calcium dependence of ryanodine-sensitive calcium channels of excitable cells

    Biophys J

    (1998)
  • S.D. Prabhu et al.

    Reactive disulfide compounds induce Ca2+ release from cardiac sarcoplasmic reticulum

    Arch Biochem Biophys

    (1990)
  • K. Otsu et al.

    Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum

    J Biol Chem

    (1990)
  • T. Jayaraman et al.

    FK506 binding protein associated with the calcium release channel (ryanodine receptor)

    J Biol Chem

    (1992)
  • E. Lam et al.

    A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor

    J Biol Chem

    (1995)
  • L. Kobzik et al.

    Nitric oxide in skeletal muscle

    Nature

    (1994)
  • R.A. Kelly et al.

    Nitric oxide and cardiac function

    Circ Res

    (1996)
  • M.B. Reid

    Role of nitric oxide in skeletal muscle: Synthesis, distribution and functional importance

    Acta Physiol Scand

    (1998)
  • D.M. Kaye et al.

    Frequency-dependent activation of a constitutive nitric oxide synthase and regulation of contractile function in adult rat ventricular myocytes

    Circ Res

    (1996)
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