Skeletal muscle excitation-contraction coupling

Cavl.l L-type CClS skeletal muscle excitation-contraction coupling, gene transcription dihydropyridines (DHPs) lethal... 

No. Voltage-gated calcium channels are found only in smooth and cardiac muscle. Excitation-contraction coupling in skeletal muscle depends on the release of intracellular calcium from the sarcoplasmic reticulum. 

It has been shown that inositol triphosphate (IP3) is involved in the excitation-contraction coupling in smooth muscle (Vergara et al., 1985), but presently no clear evidence has been reported for a similar involvement in skeletal muscle. If IP3 functions as a messenger for Ca release, it would bridge the gap between muscle metabolic changes and Ca release, as ATP is a prerequisite for IP3 regeneration. 

Schneider, M.F. Chandler, W.K. (1973). Voltage dependent charge movement in skeletal muscle A possible step in excitation-contraction coupling. Nature 242,244-246. 

A different but very interesting scenario involving L-type Ca channels is seen in skeletal muscle, where the major component of these Ca channels plays two roles. Skeletal muscle does not require extracellular Ca for excitation-contraction coupling, rather it utilizes Ca stored in the sarcoplasmic reticulum. The role of the L-type channel proteins as true Ca channels in skeletal muscle appears to be of secondary importance, but may be to provide Ca to the cells over longer periods of time. The main role of the L-type channel protein(s)... 

Tanabe T, Beam KG, Adams BA, Niidome T, Numa S 1990 Regions of the skeletal muscle dihydropyridine receptor critical for excitation-contraction coupling. Nature 346 567-569... 

Pharmacology In isolated nerve-muscle preparation, dantrolene produced relaxation by affecting contractile response of the skeletal muscle at a site beyond the myoneural junction and directly on the muscle itself. In skeletal muscle, the drug dissociates the excitation-contraction coupling, probably by interfering with the release of calcium from the sarcoplasmic reticulum. 

Skeletal muscle is not depressed by the calcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require as much transmembrane calcium influx. 

Flucher BE, Franzini-Armstrong C (1996) Formation of junctions involved in excitation-contraction coupling in skeletal and cardiac muscle. Proc Natl Acad Sci USA 93 8101-8106. 

Rios E, Brum G (1987) Involvement of dihydropyridine receptors in excitation-contraction coupling in skeletal muscle. Nature 325 717—720. 

Szentesi P, Collet C, Sarkozi S, et al. Effects of dantrolene on steps of excitation-contraction coupling in mammalian skeletal muscle fibers. J Gen Physiol. 2001 118 355-375. 

Dantrolene, a hydantoin derivative, reduces the contraction of skeletal muscle, acting directly on the muscle and not at the neuromuscular junction. It is thought to reduce the amount of calcium released and hence prevent excitation-contraction coupling (Figure 26.4). Its usefulness in the treatment of anesthetic-induced malignant hyperthermia may be due to its calcium-related uncoupling actions. 

Dantrolene is a hydantoin derivative related to phenytoin that has a unique mechanism of spasmolytic activity. In contrast to the centrally active drugs, dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers. The normal contractile response involves release of calcium from its stores in the sarcoplasmic reticulum (see Figures 13-1 and 27-10). This activator calcium brings about the tension-generating interaction of actin with myosin. Calcium is released from the sarcoplasmic reticulum via a calcium channel, sometimes called the ryanodine receptor channel because the plant alkaloid ryanodine combines with a receptor on the channel protein and, in the case of the skeletal muscle channel, locks it in the open position. 

Figure 17.5 shows a scheme for excitation-contraction coupling of a skeletal muscle. 

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). 

The close alignment of cytoplasmic and ER membranes is, in fact, cmcially important for the workings of excitation-contraction coupling in the skeletal muscle. In these cells, we have a unique mechanism of activation of one channel by another The RyR is directly hooked up to a cytosolic loop of the dihydropyridine receptor (DHPR Figure 6.6a, b). Membrane depolarization will cause a conformational change to the DHPR, which in turn is directly and mechanically transmitted to the RyR, so that both channels open synchronously. This even works in the absence of any calcium flux across the cytoplasmic membrane - experimentally, skeletal muscle cells can be induced to contract in calcium-free buffers. 

Figure 6.6. Excitation contraction coupling in skeletal muscle (a, b) and heart muscle (c). In skeletal muscle, the anesthetics receptor (DHPR) and the ryanodine receptor (RyR) are in direct contact (a). The conformational change to the former that occurs in response to membrane depolarization is sufficient to induce Ca release from the SR a flow of Ca across the plasma membrane is not necessary (b). In heart muscle, however, this direct link does not exist, and Ca must therefore enter through the DHPR first (c).

W.A. Catterall. 1991. Excitation-contraction coupling in vertebrate skeletal muscle A tale of two calcium channels Cell 64 871-874. (PubMed)... 

Dantrolene is a hydantoin class of anticonvulsant that acts outside the central nervous system to produce skeletal muscle relaxation by interfering with excitation contraction coupling. In normally contracting muscle, activation of the ryanodine receptor within the muscle fiber results in calcium release from the sarcoplasmic reticulum and subsequent muscle contraction. Dantrolene interferes with the release of calcium from the sarcoplasmic reticulum by interfering with the ryanodine receptor. The release of calcium in smooth and cardiac muscle is under different control consequently, dantrolene primarily affects skeletal muscle. 

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