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. In all muscle cells, the contraction therefore depends on an increase in the cytosolic concentration of calcium (Fig. 1). Calcium has an extracellular concentration of 2–4 mm and a resting cytosolic concentration of ∼100 nm. It is also stored in cells of the sarcoplasmic (SR, refers to skeletal and cardiac muscle) and endoplasmic (ER, refers to smooth muscle) reticulum at a concentration of ∼0.4 mm (Bootman 2012). In striated muscle, the increase in calcium levels is due to its release by SR stores via the ryanodine receptor (RyRs). Neurotransmitters such as acetylcholine bind to receptors on the muscle surface and trigger depolarization by allowing sodium/calcium ions to penetrate through the associated channels. This shifts the potential of the resting membrane to a more positive value, which in turn activates voltage-controlled channels, resulting in an action potential (the “excitation part”).
The action potential stimulates L-type calcium channels (also known as dihydropyridine receptors). In skeletal muscles, these are mechanically coupled to the SR RyR and open them directly. In the heart muscle, the influx of calcium through L-type channels opens RyRs via calcium-induced calcium release (CICR) (Bootman 2012). RyR is a large tetrameric calcium release channel with six transmembrane zones. Of the three subtypes of RyR, RyR1 is found primarily in skeletal muscle (see review by Klein et al. 1996), and RyR2 is found primarily in heart muscle (Cheng et al. 1993). The parathyroid glands, located in the neck area, release parathyroid hormone, which maintains the concentration of calcium in the blood.
To increase concentration, it mobilizes calcium stored in mineralized bones by stimulating osteoclastic activity. This works by reducing the loss of calcium ions in the kidney and increasing the reabsorption of the ion in the small intestine. We all know that calcium is essential for strong bones and teeth, but what else does it do? What about its essential role in muscle contractions, nerve impulses, blood clotting and cellular metabolism? The sarcolemma of myocytes contains many intussusceptions (pits) called transverse tubules, which are usually perpendicular to the length of the myocyte. The transverse tubules play an important role in the supply of Ca+ ions to myocytes, which are crucial for muscle contraction. It is not yet known how calsequesterin contributes to the Ca2+ release mechanism at the molecular level. However, several observations suggest that calequesterin is involved in the Ca2+ release process. For example, calequesterin has been shown to be essential for the release of Ca2+ induced by myotoxin I± by skeletal muscle SR (381). Another study shows that myotoxic drugs affect SR protein calequeestrin and the related ca2+ mitochondrial storage calmitin by increasing proteolytic degradation of these proteins (313).
In addition, in direct experiments measuring the open probability of RyR, calequesterin has been shown to increase the open probability of RyR in the presence of millimolar Ca2+ (246). 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 known 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 Î±2/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±. After its release from SR, Ca2+ binds in rapid reaction to one of the troponin subunits (TnC) that form the regulatory complex with tropomyosin on the thin filament (112, 152, 411) (Fig.7). This event is followed by a temporary development of tension on the contractile apparatus, which leads to muscle contraction. 7.Troponin (Tn) C as a myofibrillary ca2+ switch molecule. The troponin-tropomyosin-actin organizational model is according to Gagnã© et al. (145); TnC appears in blue for the NH2 domain and pink for the COOH domain. TnI appears in red (NH2 terminal domain), brown (COOH terminal domain), and yellow (inhibitory region). TnT is indicated in green. Myosin is represented in green (myosin-S1), red (essential light chain) and yellow (regulating light chain) in the representation of embroidery. Tropomyosin is represented in light blue and dark blue sticks.
Note that only TnC, myosin and tropomyosin are represented by a known structure. The TnT and TnI structures are modeled. Actin monomers are represented by white spheres. a: Organization in the relaxed state of the muscles. The COOH domain of TnC is related to Mg2+. TnI`s NH2-terminal domain is anchored in TnC`s COOH domain, while TnI`s inhibitory region and COOH-terminal domain come into contact with actin and tropomyosin. This organization keeps the thin filament in a conformation that prevents myosin from interacting properly with actin. b: Organization after two Ca2+ links to TnC`s NH2 domain, which in turn interacts with TnI. The inhibitory region and cooh domain of TnI are then released from actin. This leads to a conformation of the thin filament, which allows the correct formation of the Actomosin complex. The power stroke can then occur (not shown here) by pushing the thin filament to the right. (Image courtesy of Dr.
S. Gagnã© and Dr.B. Sykes, Edmonton, Canada.) Pv is a high-affinity Ca2+ binding protein found at high concentrations in the rapidly contraction/relaxation skeletal muscle fibers of vertebrates (examined in refs. 26, 27, 390). In rats and mice, type IIB fibers show the highest immune reactivity for PV with varying degrees of intensity (Fig. 2). The majority of type IIA fibers (60-70%) have a moderate (also graduated) coloring intensity. Other Type IIA and Type I fibres lack PV (65,144, 190, 363). The different muscle fibers of the rabbit have a very similar distribution of PV (292, 456). In human muscles, PV is detectable only in intrafusal fibers (137). TnCf binds two Ca2+ in a rapid reaction and with moderate affinity (5 to 106 Mâ1) in the NH2-terminal part of the molecule, and two other Ca2+ bind with slow kinetics and with high affinity (5 to 108 Mâ1) in the COOH-terminal part (430) (for the kinetics of ca2+ exchange, see also Fig.
8).Fig. 8.Kinetics of metal exchange with troponin C and parvalbumin. The approximate values correspond to reference 405 (see also ref. 390 for other documents). The kinetics of Ca2+ binding to troponin C (regulatory sites) and parvalbumin determines the order of flow of ca2+ released to the first troponin C, followed by parvalbumin binding in rapid skeletal muscle. For the sake of simplicity, the kinetics of troponin C`s high affinity sites is neglected. They are in the range of constants for parvalbumin. The oval symbol is used for troponin C and the square for parvalbumin. The open icons indicate the metal-free state and the solid symbols indicate the metal-loaded state. In some disease conditions, smooth muscle cells take on a non-contractile phenotype. Although these cells still have signaling machinery that increases intracellular calcium levels, they have significantly reduced calcium intake through blood pressure-driven calcium channels. Therefore, there is a shift to intracellular release of calcium fueled by storage, similar to the changes observed in cardiac hypertrophy.