Excitation-contraction coupling of skeletal muscle. A muscle fiber is excited via the nerve by an endplate potential and generates an action potential, which spreads out along the surface membrane and the transverse tubular system into the deeper parts of the muscle fiber. The dihydropyridine (DHP) receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor, which releases Ca²⁺ from the SR, a Ca²⁺ store. Ca²⁺ binds to troponin and activates the so-called contractile machinery.

Muscle endplate nicotinic AChR. The nicotinic AChR of skeletal muscle is a pentameric channel complex consisting of 2 α subunits and 1 β, 1 γ, and 1 δ subunit in fetal and denervated muscle, and 2 α subunits and 1 β, 1 δ, and 1 ε subunit in adult muscle. All subunits have a similar structure with 4 transmembrane segments, M1 to M4. They form a channel complex with each subunit contributing equally to the ion-conducting central pore formed by the M2 segments. The pore is permeable to cations. The binding site for ACh is located in the long extracellular loop of the α subunit. The 3 main conformational states of the ligand-gated channels are closed, open, and desensitized. Binding of the transmitter opens the channel from the closed state, and, during constant presence of the transmitter, desensitization occurs. Only after removal of the transmitter, the channel can recover from desensitization and subsequently will be available for another opening. Mutations associated with subtypes of CMSs are indicated by conventional 1-letter abbreviations for the replaced amino acids.

ClC-1, the major chloride channel of skeletal muscle. A membrane topology model of the ClC-1 monomer is shown. X-ray measurements and cryo-electron microscopy have elucidated the structure of the channel (104, 105) and confirmed the conclusions derived from electrophysiological results. The functional channel is an antiparallel assembled homodimer. It possesses 2 independent ion-conducting pores, each with a fast-opening mechanism of its own, 2 selectivity filters, and 2 voltage sensors (106). The channel is functional without any other subunits. Symbols are used for the mutations leading to either dominant myotonia congenita (DMC) or recessive myotonia congenita (RMC). The amino acids at which substitutions occur are indicated by 1-letter abbreviations and numbered according to the protein sequence. Adapted with permission from Nature (104).

Voltage-gated Na⁺ and Ca²⁺ channels: structure and function. The α subunit consists of 4 highly homologous domains, I–IV, with 6 transmembrane segments each (S1–S6). The S5–S6 loops and the S6 transmembrane segments form the ion-selective pore, and the S4 segments contain positively charged residues that confer voltage dependence to the protein. The S4 segments are thought to move outward upon depolarization, thereby inducing channel opening. The repeats are connected by intracellular loops; in the Na⁺ channel (A), the III–IV linker contains the supposed inactivation particle, whereas the slowly activating and inactivating L-type Ca²⁺ channel does not possess a fast-inactivation gate (C). When inserted in the membrane, the 4 repeats of the protein fold to generate a central pore. Mutations associated with the various diseases are indicated. (B) Activation, inactivation, and recovery from the fast-inactivated to the resting state are voltage- and time-dependent processes. Compared is the fast inactivation of WT and 2 mutant skeletal muscle Na⁺ channels expressed in human embryonic kidney cells: R1448H, a cold-sensitive mutation causing paramyotonia congenita, and M1360V, a temperature-insensitive mutation causing hyperkalemic periodic paralysis. The whole-cell current responses to a depolarization from –100 mV to 0 mV were superimposed at 25°C and 35°C. Adapted with permission from the Journal of Physiology (107).

Skeletal muscle RyR1. RyR1 forms a homotetrameric protein complex that is situated in the SR membrane and functions as a Ca²⁺ release channel. The cytosolic part, the “foot,” bridges the gap between the transverse tubular system and the SR. It contains binding sites for various activating ligands, like Ca²⁺ (μM), ATP (nM), calmodulin (nM), caffeine (mM), and ryanodine (nM), and inactivating ligands, like dantrolene (>10 μM), Ca²⁺ (>10 μM), ryanodine (>100 μM), and Mg²⁺ (μM). The transmembrane segments, M3–M10, are numbered according to both the earlier model of Zorzato et al. (108) and the recently modified model of MacLennan and colleagues (109). The first 2 cylinders, with dashed lines, indicate the tentative nature of the composition of the first predicted helical hairpin loop (M3–M4 or M4a–M4b). The long M7 sequence is designated as M7a and M7b. The proposed selectivity filter between M8 and M10 is designated as M9 even though it is clearly not a transmembrane sequence. Mutations causing susceptibility to MH and/or central core disease are indicated. Susceptibility to MH was defined by use of the in vitro contracture test or, in a single case, by the Japanese Ca-induced Ca release test (CICR test). MH/CC, MH with some central cores; CCD, central core disease; CCD/rods, CCD with nemaline rods.

Proposed number of control chromosomes. A statistical algorithm helps to calculate the number of controls required to minimize the error. Let the prevalence of a mutation in patient chromosomes be p₁ and the prevalence in control chromosomes be p₀. Then the probability of an arbitrary control chromosome not carrying the mutation is (1 – p₀). Because the world control population is large, the probability P of arbitrarily choosing n chromosomes thereof without the mutation may be approximated by P = (1 – p₀)ⁿ. The null hypothesis would be that the mutation frequency is equal in patient and control chromosomes, i.e., p₀ = p₁ and P = (1 – p₁)ⁿ. The number of control chromosomes to be tested can be calculated by resolution of the equation for the number n = ln(P)/ln(1 – p₁). When the error probability P is set at 1%, the number of required control chromosomes is n = –4.6/ln(1 – p₁) and n = 460 for the example of p₁ = 1%. The curve demonstrates that 100 control individuals (200 chromosomes) would be adequate for a p₁ of 2.5%, a prevalence that is much higher than that of the most frequent monogenic disorder. Adapted with permission from Neurology (90).