Muscle ryanodine receptor

Avila, G., and Dirksen, R. T. (2001a). Functional Effects of Central Core Disease Mutations in the Cytoplasmic Region of the Skeletal Muscle Ryanodine Receptor. J Gen Physiol 118(3) 277—90. Avila, G., O Brien, J. J., and Dirksen, R. T. (2001b). Excitation-Contraction Uncoupling by a Human Central Core Disease Mutation in the Ryanodine Receptor. Proc Natl AcadSci USA 98(7) 4215—20. Avila, G., O Connell, K. M., Dirksen, R. T. (2003). The Pore Region of the Skeletal Muscle Ryanodine Receptor is a Primary Locus for Excitation-Contraction Uncoupling in Central Core Disease. J Gen Physiol 121(4) 277-86. 

Dirksen, R., and Avila, G. (2004). Pathophysiology of Muscle Disorders Linked to Mutations in the Skeletal Muscle Ryanodine Receptor. New York, Kluwer Academic Publisher. 

McWilliams, S., Nelson, T., Sudo, R. T., Zapata-Sudo, G., Batti, M., and Sambuughin, N. (2002). Novel Skeletal Muscle Ryanodine Receptor Mutation in a Large Brazilian Family with Malignant Hyperthermia. Clin Genet 62(1) 80—3. 

Monnier, N., Romero, N. B., Lerale, J., Landrieu, P., Nivoche, Y., Fardeau, M., and Lunardi, J. (2001). Familial and Sporadic Forms of Central Core Disease are Associated with Mutations in the C-Terminal Domain of the Skeletal Muscle Ryanodine Receptor. Hum Mol Genet 10(22) 2581—92. 

Zorzato, F., Yamaguchi, N., Xu, L., Meissner, G., Muller, C. R., Pouliquin, P., Muntoni, F., Sewry, C., Girard, T., andTreves, S. (2003). Clinical and Functional Effects of a Deletion in a COOH-Terminal Lumenal Loop of the Skeletal Muscle Ryanodine Receptor. Hum Mol Genet 12(4) 379-88. 

Otsu K, Khanna VK, Archibald AL, MacLennan DH. Cosegregation of porcine malignant hyperthermia and a probable causal mutation in the skeletal muscle ryanodine receptor gene in backcross families. Genomics 1991 11(3) 744-750. 

The skeletal muscle ryanodine receptor, RyRl, controls the release of calcium, through a central channel, from the intracellular sarcoplasmic reticulum [34], The channel forms at the convergence of four identical protein subunits each of which contains two a-helices. One helix from each subunit is approximately 0.45 nm long and has a central kink. The overall effect is to give the channel a funnel-like entrance about 0.3 nm across leading to a central pore with a 0.15 nm diameter. The pore is defined by four further a-helices approximately 0.22 nm long, one from each subunit. Unfortunately the low resolution of the structure does not allow for detailed study of the filtering mechanism. 

While skeletal muscle ryanodine receptors are involved in excitation — contraction coupling through direct interactions with voltage-gated Ca2+ channels, in other cell types ryanodine receptor Ca2+ channels located on the ER membrane are opened by cADPR in a Ca2+-CaM-dependent fashion. Ca2+ and plant metabolites such as the diterpenoid alkaloid ryanodine and the methylxanthine caffeine promote opening of the ryanodine receptor Ca2+ channel. Ryanodine can also negatively modulate the receptor (Table 4.4). 

Kimura T, Nakamori M, Lueck JD, PouUquin P, Aoike F et al (2005) Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmrc reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum Mol Genet 14 2189-2200 Kishore S, Stamm S (2006) The snoRNA HBll-52 regulates alternative splicing of the serotonin receptor 2C. Science 311 230-232... 

Malignant hyperthermia is a frequently fatal condition that involves severe muscle contraction and hyperthermia. Episodes are triggered by stress and/or specific volatile anesthetics, such as halothane, which cause excessive calcium release from the sarcoplasmic reticulum. The disorder is caused by a mutation in the skeletal muscle ryanodine receptor. The physiological mechanism by which stress triggers malignant hyperthermia is not fully understood. 

Susceptibility relates to a mutation in RyR-1, the gene encoding the skeletal muscle ryanodine receptor (RYR-1) other loci have been identified on the L-type Ca + channel and on associated proteins. 

Fruen et al. Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. / Biol Chem 1997 272(43) 26965. 

Bellinger, A.M., Mongillo, M., and Marks, A.R. (2008) Stressed out The skeletal muscle ryanodine receptor as a target of stress./owma/ of Clinical Investigation, 118, 445 53. 

Sorcin (soluble resistance-related calcium binding protein) was isolated from multidrug-resistant cells and is expressed in a few mammalian tissues such as skeletal muscle, heart, and brain. In the heart, sorcin interacts with the ryanodine receptor and L-type Ca2+-channels regulating excitation in contraction coupling. 

Ca2+ sparks are localized and transient Ca2+ release observed recurrently in muscle cells and skinned fibres. A Ca2+ spark is considered to be the elementary process of Ca2+ release in situ from one to a few ryanodine receptors. 

Calsequestrin is the major calcium storage protein of the sarcoplasmic reticulum in skeletal and cardiac muscles. It is highly acidic and has a large capacity for Ca2+. Calsequestrin functions to localize calcium near the junctional face of the terminal cistemae from which calcium can be released into the cytosol via the ryanodine receptor. 

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder that is triggered by exposure to inhalation of general anesthetics, such as halothane. In susceptible individuals, these drugs can induce tachycardia, a greatly increased body metabolism, muscle contracture and an elevated body temperature (above 40°C) with a rapid rate of increase. Many cases of MH are linked to a gene for type 1 ryanodine receptor (RyRl). 

Franzini-Armstrong C, Protasi F (1997) Ryanodine receptor of striated muscles a complex channel capable of multiple interactions. Physiol Rev 77 699-672... 

S100A1 is the most abundant in the myocardium but is also expressed in brain and other tissues. S100A1 was found to stimulate Ca2+-induced Ca2+-release (CICR) in skeletal muscle terminal cisternae. In the presence of nanomolar Ca2+-concentrations, S100A1 binds to the ryanodine receptor increasing its channel open probability, and was shown to enhance SR Ca2+-release and contractile performance. Several animal models (over expressing S100A1 or S100A1-deficient mice) have... 

Sarcoplasmic reticulum (SR) is a form of the smoothfaced endoplasmic reticulum (ER) in muscles. It functions as an intracellular Ca2+ store for muscle contraction. Ca2+ is energetically sequestered into the SR by Ca2+-pump/sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) and released via Ca2+ release channels on stimuli (ryanodine receptor in striated muscles and inositol 1,4,5-trisphosphate receptor in most smooth muscles). Endoplasmic reticulum in non-muscle tissues also functions as an intracellular Ca2+ store. 

In striated muscles, SR is well developed to surround the myofibrils and is divided into two parts, the terminal cisternae (TC) and longitudinal tubules (LT). TC forms triad (skeletal muscle) or dyad (heart) structure with transverse tubules. The ryanodine receptor is located only in the TC, whereas the Ca2+ pump/SERCA is densely packed in both TC and LT. 

Harioka, T., Sone, T., Toda, H. (1990). Ca release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. J. Biol. Chem. 265, 2244-2256. 

Figure 49-8. Diagram of the relationships among the sarcolemma (plasma membrane), a T tubule, and two cisternae of the sarcoplasmic reticulum of skeletal muscle (not to scale). The T tubule extends inward from the sarcolemma. A wave of depolarization, initiated by a nerve impulse, is transmitted from the sarcolemma down the T tubule. It is then conveyed to the Ca release channel (ryanodine receptor), perhaps by interaction between it and the dihydropyridine receptor (slow Ca voltage channel), which are shown in close proximity. Release of Ca from the Ca release channel into the cytosol initiates contraction. Subsequently, Ca is pumped back into the cisternae of the sarcoplasmic reticulum by the Ca ATPase (Ca pump) and stored there, in part bound to calsequestrin.

Calcium couples muscle membrane excitation to filament contraction. Important work has focused on the proteins present in the T-tubule/SR junction. One protein, an integral component of the T-tubular membrane, is a form of L-type, dihydropyridine-sensitive, voltage-dependent calcium channel. Another, the ryanodine receptor (RyR), is a large protein associated with the SR membrane in the triad that may couple the conformational changes in the Ca2+ channel protein induced by T-tubular depolarization to the Ca2+ release from the SR (Fig. 43-6). 

The first molecule, the Ca2+ channel, is required for coupling at the triad. Skeletal muscle contains higher concentrations of this L-type Ca2+ channel that can be accounted for on the basis of measured voltage-dependent Ca2+ influx because much of the Ca2+ channel protein in the T-tubular membrane does not actively gate calcium ion movement but, rather, acts as a voltage transducer that links depolarization of the T-tubular membrane to Ca2+ release through a receptor protein in the SR membrane. The ryanodine receptor mediates sarcoplasmic reticulum Ca2+ release. The bar-like structures that connect the terminal elements of the SR with the T-tubular membrane in the triad are formed by a large protein that is the principal pathway for Ca2+ release from the SR. This protein, which binds the... 

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