The role of ion-regulatory membrane proteins of excitation-contraction coupling and relaxation in inherited muscle diseases (original) (raw)
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Action Potential in the Transverse Tubules and Its Role in the Activation of Skeletal Muscle
The Journal of General Physiology, 1974
The double sucrose-gap method was applied to single muscle fibers of Xenopus. From the "artificial node" of the fiber, action potentials were recorded under current-clamping condition together with twitches of the node. The action potentials were stored on magnetic tape. The node was then made inexcitable by tetrodotoxin or by a sodium-free solution, and the wave form of the action potential stored on magnetic tape was imposed on the node under voltage-clamp condition (simulated AP). The twitch height caused by the simulated AP's was always smaller than the twitch height produced by the real action potentials, the ratio being about 0.3 at room temperature. The results strongly suggest that the transverse tubular system is excitable and is necessary for the full activation of twitch, and that the action potential of the tubules contributes to about 70 % of the total mechanical output of the normal isotonic twitch at 20°C. Similar results were obtained in the case of tet...
Voltage change‐induced gating transitions of the rabbit skeletal muscle Ca2+ release channel
1998
Excitation-contraction (E-C) coupling in skeletal muscle is thought to involve the concerted action of at least two membrane proteins: (i) the dihydropyridine receptor (DHPR) of the transverse tubule membrane, which is assumed to function as both a voltage sensor and a signal transducer that receives and communicates the signal of transverse tubule depolarization towards the sarcoplasmic reticulum (SR), and (ii) the ryanodine receptor Ca¥ release channel (RyRC), which on the SR side is activated upon receipt of the signal from the DHPR (
The Journal of Physiology, 2005
Using a two-microelectrode voltage clamp technique, we investigated possible mechanisms underlying the impaired excitation-contraction coupling in skeletal muscle fibres of the mdx mouse, a model of the human disease Duchenne muscular dystrophy. We evaluated the role of the transverse tubular system (T-system) by using the potentiometric indicator di-8 ANEPPS, and that of the sarcoplasmic reticulum (SR) Ca2+ release by measuring Ca2+ transients with a low affinity indicator in the presence of high EGTA concentrations under voltage clamp conditions. We observed minimal differences in the T-system structure and the T-system electrical propagation was not different between normal and mdx mice. Whereas the maximum Ca2+ release elicited by voltage pulses was reduced by approximately 67% in mdx fibres, in agreement with previous results obtained using AP stimulation, the voltage dependence of SR Ca2+ release was identical to that seen in normal fibres. Taken together, our data suggest that the intrinsic ability of the sarcoplasmic reticulum to release Ca2+ may be altered in the mdx mouse.
The Journal of physiology, 2009
In striated muscle, activation of contraction is initiated by membrane depolarisation caused by an action potential, which triggers the release of Ca(2+) stored in the sarcoplasmic reticulum by a process called excitation-contraction coupling. Excitation-contraction coupling occurs via a highly sophisticated supramolecular signalling complex at the junction between the sarcoplasmic reticulum and the transverse tubules. It is generally accepted that the core components of the excitation-contraction coupling machinery are the dihydropyridine receptors, ryanodine receptors and calsequestrin, which serve as voltage sensor, Ca(2+) release channel, and Ca(2+) storage protein, respectively. Nevertheless, a number of additional proteins have been shown to be essential both for the structural formation of the machinery involved in excitation-contraction coupling and for its fine tuning. In this review we discuss the functional role of minor sarcoplasmic reticulum protein components. The defi...
Proceedings of the National Academy of Sciences, 2007
Stimuli are translated to intracellular calcium signals via opening of inositol trisphosphate receptor and ryanodine receptor (RyR) channels of the sarcoplasmic reticulum or endoplasmic reticulum. In cardiac and skeletal muscle of amphibians the stimulus is depolarization of the transverse tubular membrane, transduced by voltage sensors at tubular-sarcoplasmic reticulum junctions, and the unit signal is the Ca 2؉ spark, caused by concerted opening of multiple RyR channels. Mammalian muscles instead lose postnatally the ability to produce sparks, and they also lose RyR3, an isoform abundant in spark-producing skeletal muscles. What does it take for cells to respond to membrane depolarization with Ca 2؉ sparks? To answer this question we made skeletal muscles of adult mice expressing exogenous RyR3, demonstrated as immunoreactivity at triad junctions. These muscles showed abundant sparks upon depolarization. Sparks produced thusly were found to amplify the response to depolarization in a manner characteristic of Ca 2؉induced Ca 2؉ release processes. The amplification was particularly effective in responses to brief depolarizations, as in action potentials. We also induced expression of exogenous RyR1 or yellow fluorescent protein-tagged RyR1 in muscles of adult mice. In these, tag fluorescence was present at triad junctions. RyR1-transfected muscle lacked voltage-operated sparks. Therefore, the voltageoperated sparks phenotype is specific to the RyR3 isoform. Because RyR3 does not contact voltage sensors, their opening was probably activated by Ca 2؉ , secondarily to Ca 2؉ release through junctional RyR1. Physiologically voltage-controlled Ca 2؉ sparks thus require a voltage sensor, a master junctional RyR1 channel that provides trigger Ca 2؉ , and a slave parajunctional RyR3 cohort.
The excitation–contraction coupling mechanism in skeletal muscle
Biophysical Reviews, 2014
First coined by Alexander Sandow in 1952, the term excitation-contraction coupling (ECC) describes the rapid communication between electrical events occurring in the plasma membrane of skeletal muscle fibres and Ca 2+ release from the SR, which leads to contraction. The sequence of events in twitch skeletal muscle involves: (1) initiation and propagation of an action potential along the plasma membrane, (2) spread of the potential throughout the transverse tubule system (T-tubule system), (3) dihydropyridine receptors (DHPR)-mediated detection of changes in membrane potential, (4) allosteric interaction between DHPR and sarcoplasmic reticulum (SR) ryanodine receptors (RyR), (5) release of Ca 2+ from the SR and transient increase of Ca 2+ concentration in the myoplasm, (6) activation of the myoplasmic Ca 2+ buffering system and the contractile apparatus, followed by (7) Ca 2+ disappearance from the myoplasm mediated mainly by its reuptake by the SR through the SR Ca 2+ adenosine triphosphatase (SERCA), and under several conditions movement to the mitochondria and extrusion by the Na + /Ca 2+ exchanger (NCX). In this text, we review the basics of ECC in skeletal muscle and the techniques used to study it. Moreover, we highlight some recent advances and point out gaps in knowledge on particular issues related to ECC such as (1) DHPR-RyR molecular interaction, (2) differences regarding fibre types, (3) its alteration during muscle fatigue, (4) the role of mitochondria and store-operated Ca 2+ entry in the general ECC sequence, (5) contractile potentiators, and (6) Ca 2+ sparks.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2005
Chronic low-frequency stimulation of rabbit tibialis anterior muscle over a 24-h period induces a conspicuous loss of isometric tension that is unrelated to muscle energy metabolism (J.A. Cadefau, J. Parra, R. Cusso, G. Heine, D. Pette, Responses of fatigable and fatigueresistant fibres of rabbit muscle to low-frequency stimulation, Pflugers Arch. 424 (1993) 529-537). To assess the involvement of sarcoplasmic reticulum and transverse tubular system in this force impairment, we isolated microsomal fractions from stimulated and control (contralateral, unstimulated) muscles on discontinuous sucrose gradients (27-32-34-38-45%, wt/wt). All the fractions were characterized in terms of calcium content, Ca 2+ /Mg 2+ -ATPase activity, and radioligand binding of [ 3 H]-PN 200-110 and [ 3 H]ryanodine, specific to dihydropyridine-sensitive calcium channels and ryanodine receptors, respectively. Gradient fractions of muscles stimulated for 24 h underwent acute changes in the pattern of protein bands. First, light fractions from longitudinal sarcoplasmic reticulum, enriched in Ca 2+ -ATPase activity, R 1 and R 2 , were greatly reduced (67% and 51%, respectively); this reduction was reflected in protein yield of crude microsomal fractions prior to gradient loading (25%). Second, heavy fractions from the sarcoplasmic reticulum were modified, and part (52%) of the R 3 fraction was shifted to the R 4 fraction, which appeared as a thick, clotted band. Quantification of [ 3 H]-PN 200-110 and [ 3 H]ryanodine binding revealed co-migration of terminal cisternae and t-tubules from R 3 to R 4 , indicating the presence of triads. This density change may be associated with calcium overload of the sarcoplasmic reticulum, since total calcium rose three-to fourfold in stimulated muscle homogenates. These changes correlate well with ultrastructural damage to longitudinal sarcoplasmic reticulum and swelling of ttubules revealed by electron microscopy. The ultrastructural changes observed here reflect exercise-induced damage of membrane systems that might severely compromise muscle function. Since this process is reversible, we suggest that it may be part of a physiological response to fatigue. D