Neuromuscular

ION CHANNEL, TRANSMITTER, & RECEPTOR DISEASES

Channel disorders
Calcium
Chloride
Concepts
Long QT Syndromes
Potassium
Sodium
Transmitters & Receptors
Acetylcholine
Catecholamines
Dopamine
Glycine

Chloride channels Sodium channels Calcium channels Potassium channels Acetylcholine Receptors Glycine receptors Dopamine receptors

Long QT Syndromes

Concepts in channelopathies

What are the properties of the mutations in the chloride channel gene (CLC1) that determine whether a syndrome is inherited in a dominant or recessive pattern?

The dominant or recessive nature of a mutation depends on the ability of the mutant chloride channel monomers to polymerize with normal channel monomers. Dominant mutations complex with normal monomers producing defective channels. For some mutations one abnormal monomer is sufficient to destroy the function of a tetramer complex (e.g. Pro480Leu). For other mutations (e.g. Gly230Glu) it requires two abnomal monomers to destroy the channel function of a tetramer. In either case, only a minority of tetramers remain functional and myotonia results. Recessive mutations do not complex with normal monomers. Normal monomers are then free to complex with other normal monomers. This produces enough functional tetramers in heterozygotes (50% of the usual amount) to preserve normal membrane excitablity and myotonia does not occur.



What are the properties of the mutations in the sodium channel gene (SCN4A) that determine whether a syndrome presents with myotonia, paramyotonia, or weakness?

Many mutations produce abnormal inactivation of the sodium channel. This results in increased sodium conductance and membrane depolarization. Mild depolarization is associated with increased membrane excitability and myotonia. Strong depolarization produces membrane inexcitability and weakness. Some mutations only reduce inactivation at low temperatures producing paramyotonic disorders (myotonia or weakness worse in the cold). Mutations in the inactivation gate (amino acid 1306) produce different degrees of disease severity depending on the size and charge of the side chain of the new amino acid. Alanine, with a short side chain produces mild myotonia fluctuans. Valine, with an intermediate side chain, produces paramyotonia congenita. Glutamic acid, with a long side chain and a negative charge, results in myotonia permanens.



CHANNEL TOXINS

Ciguatoxin Conotoxins Lidocaine Saxitoxin Tetrodotoxin

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1/27/97

References
1. TINS Supplement: June 1996