Biomedical Engineering Reference
In-Depth Information
spacer by a butyl or ethyl led to dramatic reduction in the potency of the
compounds. In the case of NPPB class of compounds, which also have a nitro
group at the meta-position with respect to carboxylate group, the distance between
this nitro group and the carboxylate group was also found to be important. These
observations lead to suggest that chloride channel blockers interact with several
sites of the channel.
However, this nitro group is found to be possessed by only the chloride channel
blockers. The blockers of Na
2+
/2Cl
/K
+
carrier contain instead a sulfonamide group
as in furosemide (18) and piretanide (19), or a pyridine ring as in triflocine (20)
and torasemide (21). All other groups, namely, a carboxylate group, an amino group,
and an apolar moiety are commonly essential for both the classes of blockers [
166
].
5 Conclusion
Chloride ion channels have been found to play crucial roles in the development of
human diseases. They have been classified into different groups based on their
gating mechanisms that depend on changes in the membrane electrical potential,
activation of a protein kinase, increase in intracellular Ca
2+
levels and binding of
a ligand. Thus, there are four groups of Cl
channels termed chloride ion channels
(CLC channels), cystic fibrosis transmembrane regulator (CFTR), Ca
2+
-activated
chloride (CaCC) channels, and ligand-gated chloride ion channels (LGICs). How-
ever, a new class of Cl
channels known as CLICs has also been reported. Further,
another class of Cl
channels is constituted of bestrophins, a group of proteins,
which have been found to support Cl
channel activity when overexpressed in cell
expression.
CLC chloride channels constitute the only class of Cl
channels that are
conserved from bacteria to man. The crystal structure of two bacterial proteins
pictured out a dimer with two identical subunits, each composed of 18
a
-helices,
most of which do not cross the membrane entirely. CFTR is a cyclic-AMP activated
plasma membrane chloride channel that has also been assumed to function as
a chloride channel in intracellular organelles. CFTR has been found to act as
a regulator of other ion channels, for example, Na
+
and Cl
. As far as its structure
is concerned, it has been found to possess 12 transmembrane domains, two NBFs,
and a regulatory R domain. The Ca
2+
-activated chloride channels (CaCC Channels)
are found in many cell types, for example, epithelial cells, neurons, cardiac cells,
smooth muscle cells, and blood cells. They play an important role in epithelial cells
as a transepithelial transporter. The ligand-gated Cl
channels (LGICs) open in
response to specific ligand molecules binding to extracellular domain of the receptor
protein. The two important LGICs are pentameric proteins, in which each subunit
has a large extracellular domain at the N-end, four transmembrane segments, and
an intracellular loop (Fig.
3
). The LGICs are also called ionotropic receptors.
The CLICs are the proteins that function as intracellular chloride ion channels.
There are several members in CLIC family of proteins. All CLICs share structural
