Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 23Jul99
5. ION CHANNEL GENES AND HUMAN NEUROLOGICAL DISEASE
Ion channels are protein channels in cell membranes that allow
ions to pass from extracellular solution to intracellular
solution and vice versa. Most ion channels involve a number of
different associated protein subunits forming a discrete pore in
the cell surface. Most ion channels are selective, allowing only
certain ions to pass, and an individual cell has ion channels
with various ion selectivities. The selectivity of an ion channel
can be "gated", the channel effectively opened or closed, and ion
channels are said to "*voltage-gated" or "*ligand-gated",
depending on how the change in selectivity is provoked. Progress
in the study of ion channels has made it possible to analyze the
effects of human neurological disease-causing channel mutations
at various levels: the single channel, the subcellular domain,
the neuronal network, and the behaving organism.
... ... E.C. Cooper and L.Y. Jan present a review of recent
research relating ion channel genes to human neurological
disease, the authors making the following points:
1) Clinicians and geneticists seeking the causes of
neurological disorders have mapped chromosomal loci for
hereditary diseases and have found at these loci both previously
unknown channel genes and pathogenic mutations in known channel
genes. This work has proceeded rapidly. The first ion channel
disease mutations, those associated with *hyperkalemic periodic
paralysis, were identified in 1991. Now the list includes
hundreds of disease-causing gene entities responsible for more
than 20 nerve and muscle disorders. Meanwhile, advances in many
disciplines, including electrophysiology, cell biology, genomics,
neuroanatomy, and structural biology have deepened our
understanding of how ion channels function at the molecular and
cellular level, so that it is now possible to approach the
question of how channel gene mutations cause particular types of
neurological symptoms.
2) Molecular cloning has revealed a large number of channel
genes, and apparently this expansion began early in evolution.
The genome of the *nematode worm Caenorhabditis elegans contains
approximately 80 potassium channel genes, 90 ligand-gated channel
genes, 5 voltage-gated calcium-channel genes, 6 cyclic
nucleotide-gated channel genes, and 6 chloride channel genes.
These numbers do not include the many and variable channel
auxiliary subunits that make important contributions to channel
function. Homologues of a large portion of the C. elegans channel
genes have already been found in mammals.
3) The characterization of the expressed products of ion
channel genes in general, and of the channel mutations that cause
neurological diseases, is a relatively new research effort. A
large variety of disease phenotypes apparently may result from
mutations in channels functioning together at a single anatomical
site such as the *neuromuscular synapse. In the brain, a far
greater variety of channels are expressed, and the roles played
by specific channels are for the most part poorly understood. But
studies of several brain channel disorders indicate that subtle
changes in the electrophysiological properties of a single
channel type can have important effects on behavior.
4) In the future, while neurobiologists illuminate the links
between individual genes and behavior, structural biologists and
pharmacologists will characterize in new detail the molecular
character of the different channel proteins and identify
compounds that modify the activity of individual channel types.
In 1998, this effort entered a period of accelerating progress,
as in that year the structure of a bacterial potassium channel
was solved by x-ray crystallography, and the structures of
components of eukaryotic channels involved in gating, subunit
association, and ligand binding also were determined.
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E.C. Cooper and L.Y. Jan: Ion channel genes and human
neurological disease: Recent progress, prospects, and challenges.
(Proc. Natl. Acad. Sci. US 27 Apr 99 96:4759)
QY: Lily Yeh Jan [gkw at itsa.ucsf.edu]
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Text Notes:
... ... *voltage-gated: Refers to the opening or closing of an
ion channel by changes in the electrical potential across the
cell membrane.
... ... *ligand-gated: Refers to the opening and closing of an
ion channel by interactions between ligands and membrane
receptors.
... ... *hyperkalemic periodic paralysis: A disease characterized
by defective voltage-gated calcium channels producing sustained
membrane depolarization.
... ... *nematode worm Caenorhabditis elegans: A nematode worm
is a member of an abundant and ubiquitous phylum of
unsegmented roundworms. Caenorhabditis elegans is a small (1 mm)
nematode worm. It is transparent, hermaphroditic, free-living,
and found in soil. It has a relatively small genome
(approximately 3000 genes), and only a few types of cells in its
body. It has a 16-hr embryogenesis that can be achieved in a
petri dish, and is thus highly suitable for the study of
developmental and behavioral genetics.
... ... *neuromuscular synapse: (neuromuscular junction;
myoneural junction) The neuromuscular junction is an anatomically
specialized area of contact between the axon terminal of a motor
neuron and the surface membrane of a muscle fiber (muscle cell).
In general, a "motor" neuron is a neuron that conveys nerve
impulses (action potentials) from the central nervous system to
either muscles or glands. The axon of nerve cell is the usually
long extension along which action potentials are propagated.
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Summary & Notes by SCIENCE-WEEK [http://scienceweek.com] 23Jul99
