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Muscle contraction is known to be regulated by calcium. An action potential generated by a motor neuron spreads to the surface of the muscle cell, activating voltage-dependent calcium channels and allowing calcium to flow into the muscle cell. This calcium activates another ion channel called the ryanodine receptor (RyR1 in muscle cells), which releases even more calcium stored in the sarcoplasmic reticulum into the cell`s cytoplasm. The diffusion of calcium in the cytoplasm between the myosin and actin filaments of the muscle fibrils causes the filaments to slide into each other and triggers the contraction of the entire muscle fiber. When the action potential decays, calcium ions are actively pumped into the sarcoplasmic reticulum with the SERCA pump (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase). RyR, to which the plant alkaloid ryanodin specifically binds, is the main channel for the release of Ca2+ from intracellular reserves in skeletal muscle; it is involved in the release of Ca2+ induced by tubular depolarization t from the SR (Fig.4). There are several review articles on the structure and function of RyR (74, 131.324, 458). In skeletal muscles, the activation of Ca2+ release by the SR is controlled by a tension sensor in the transverse tubular membrane (TT) (459). Elementary Ca2+ signaling events have recently been subcellularly localized in skeletal muscle.

These signals represent individual RyR openings in the SR membrane and have been called Ca2+ sparks or Ca2+ quarks (verified in ref.371). The initial release of Ca2+ activates additional Ca2+ sparks via the ca2+ induced ca2+ release by the SR. It is now believed that the transmission of the signal from DHPR to RyR is carried out by mechanical coupling. This is fully consistent with schneider and Chandler`s (459) original assumption that charged components move through the sarcolemma and T tubules in response to depolarization and this is coupled to a charged component in the SR. The fact that asymmetric charge movement is related to excitation-contraction coupling has been proven by numerous studies. For example, in the soleus muscle of paraplegic rats (after spinal cord transsection), dependence on contraction tension (K+ contractions and contractures) and load movements have been shown to change in parallel compared to normal animals (109). Another study shows that T3, which shifts soleus muscles to rapid physiology, also increases the amount of load movement and shifts both the voltage dependence of the charge movement and the tension to more positive potentials (110). The activation induced by voltage-dependent depolarization is independent of a ca2+ input current (see ref.

64). However, maintaining the function of the voltage sensor depends on the external Ca2+. It appears that Ca2+ has a stabilizing effect that promotes the coupling of excitation and contraction (EC) (discussed in refs. 340, 458). In contrast, during EC coupling, the RyR heart muscle (RyR2) is activated by the influx of Ca2+ through the DHPR, a phenomenon called Ca2+ release induced by ca2+ (see Ref. 123). Since the influx of Ca2+ through the Ca2+ sensor is of secondary importance for the physiology of skeletal muscles, this mechanism is not discussed in this article.Fig. 4.The ryanodine receptor and its function in the release of Ca2+. Proposed arrangement of proteins in the SR and target proteins of Ca2+ in the cytoplasm. The transverse tubular membrane is part of the plasma membrane of the muscle fiber. The interaction of the α subunit of the Ca2+ channel, also known as the dihydropyridine receptor (DHPR), and the Ca2+ release channel of the SR called the ryanodine receptor (RyR1) connects the two membranes, the tubular membranes and SR.

This compound is responsible for electromechanical coupling. Several cytoplasmic and SR proteins are associated with the DHP/RyR complex (triadine, calequesterin, binding protein FK506 and calmodulin). The release of calcium by SR via RyR1 triggers muscle contraction and several cellular effects by binding ca2+ to a variety of other target proteins. The reuptake of Ca2+ from the cytoplasm into the SR is carried out by the SR calcium pump. The second messenger no has been proposed to play a role in the relaxation of rapidly contracting muscle fibers (266). NO inactivates m-calpain at neutral pH (348). In contrast, the activity of calpain Î1/4 was only affected by NO when the pH was moved to acidic levels, a condition that does not inhibit m-calpain by NO. Therefore, it could be assumed that NO can selectively affect calpain isoforms based on the concentration of hydrogen ions in contracting muscles under physiological and pathological conditions. Interestingly, NO synthase, which is present in muscle at the highest frequency, is the Ca2+/CaM-dependent type (42). Therefore, the activity of calpaine could be regulated by Ca2+ by CaM/NO synthase (for caM targets, see section iiiA and Table 2). To complete the discussion on MH, a brief overview of the other MH candidate locomotives that have nothing to do with the RyR locus is given. As mentioned above, mutations in the RyR1 gene (chromosome 19q13.1) represent only a subset of MHS cases.

This first gene locus for MHS was called MHS1. Based on genetic coupling studies, there is evidence of at least five other MHS loci, designated as MHS2 (chromosome 17q11.2-q24, ref. 300), MHS3 (chromosome 7q, ref. 222), MHS4 (chromosome 3q13.3, ref. 503), MHS5 (chromosome 1q31, ref. 356) and MHS6 (chromosome 5p, ref. 431). Candidate genes exist for some loci (Table 2). The MHS3 locus contains a chromosomal segment that contains the gene for the α2/Î` subunit of the L-type Ca2+ channel of skeletal muscle, but no mutations have been found in the gene. In any event, the binding data provided evidence of considerable heterogeneity in MHS. Recently, MHS5 was confirmed as an independent MHS locus following the discovery of a mutation in the CACLN1A3 gene (356) encoding the L-type muscle calcium channel subunit I±. A change in receptor conformation causes an action potential that activates the voltage-controlled L-type calcium channels present in the plasma membrane.

The influx of calcium from L-type calcium channels activates ryanodine receptors to release calcium ions from the sarcoplasmic reticulum. This mechanism is called calcium-induced calcium release (CICR). It is not known whether the physical opening of L-type calcium channels or the presence of calcium causes ryanodine receptors to open. The flow of calcium allows the myosin heads to access the binding sites of the transverse actin bridge, which allows muscle contraction. ACh is broken down into acetyl and choline by the enzyme acetylcholinesterase (AChE). AChE is located in the synaptic cleft and breaks down ACh so that it does not remain bound to ACh receptors, which would lead to prolonged unwanted muscle contraction. Denervation of slow contractions and rapid contractions of the muscle leads to downregulation of SERCA2a or SERCA1. The expression of the alternative isoform was not affected by denervation. Physiological parameters, for example. B the contraction time, have changed steadily with the reduction in atpase activity (461), although it should be noted that many other proteins that modify contractile properties are also modified in their expression. Fig.

4.The ryanodine receptor and its function in the release of Ca2+. Proposed arrangement of proteins in the SR and target proteins of Ca2+ in the cytoplasm. The transverse tubular membrane is part of the plasma membrane of the muscle fiber. The interaction of the α subunit of the Ca2+ channel, also known as the dihydropyridine receptor (DHPR), and the Ca2+ release channel of the SR called the ryanodine receptor (RyR1) connects the two membranes, the tubular membranes and SR. This compound is responsible for electromechanical coupling. Several cytoplasmic and SR proteins are associated with the DHP/RyR complex (triadine, calequesterin, binding protein FK506 and calmodulin). The release of calcium by SR via RyR1 triggers muscle contraction and several cellular effects by binding ca2+ to a variety of other target proteins. The reuptake of Ca2+ from the cytoplasm into the SR is carried out by the SR calcium pump. Many, but not all, dystrophies are diseases of the dystrophin-glycoprotein complex and are now classified as dystrophinopathies.

Human Duchenne muscular dystrophy (DMD) is best known because it is one of the most common human genetic diseases (â1/41: 3,500 male births; No. 202). The main defect of DMD is the lack of dystrophin, a subskeletal cytoskeletal protein with 427-kDa. In normal muscle, it connects the cytoskeleton (actin) via a complex of membrane proteins (glycoproteins associated with dystrophin, e.B. dystroglycans and sarcoglycans) with laminin in the extracellular matrix (Fig. 13) (62). The absence of dystrophin is due to mutations in the dystrophin gene, which is extraordinarily large (>2,300 kB) and located on the X chromosome in Xp21 (Table 2). More than 1,500 deletion breakpoints have been detected in the human dystrophin gene in European populations alone (83). There are several animal models of muscular dystrophy, including mouse X-linked dystrophy, mdx (49,202). Today, it seems clear that all patients with DMD lack dystrophin, regardless of the underlying mutation, and it is believed that the lack of dystrophin causes the phenotype of dystrophy.

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