Chloride Ion Channels: Structure, Functions, and Blockers - Ion Channels and Their Inhibitors - page 311

variety of biological processes that involve changes in the cells. Such processes are,
for example, cardiac, skeletal, and smooth muscle contraction, epithelial transport
of nutrient -cell insulin release. The

overactivation of these channels leads to several diseases and hence their inhibitors
constitute several important classes of drugs.
Ion channels have been named depending upon what ion they let pass (e.g., Na + ,
K + ,Ca 2+ ,Cl ). Among them, chloride ion channels are pore-forming membrane
proteins that allow the passive transport of Cl across biological membranes. They
are ubiquitously expressed in almost all eukaryotic cells [ 1 ]. Voltage-gated and
ligand-gated ion channels represent major classes of pharmacological receptors [ 2 ].
Voltage-gated ion channels open and close in response to membrane potential and
ligand-gated ion channels (LGICs), also called ionotropic receptors, open in
response to specific ligand molecules binding to the extracellular domains of the
receptor protein. Ligand binding causes a conformational change in the structure of
the channel protein that ultimately leads to the opening of the channel gate and the
subsequent ion flux across the plasma membrane. Chloride ion channels involve
both the mechanism, voltage-gated and ligand-gated, to transport the ions.
Chloride ion channels have been found to play crucial roles in the development
of human diseases [ 3 ]. Mutations in the genes encoding Cl channels have been
found to be responsible for the development of a variety of deleterious diseases in
muscle, kidney, bone, and brain, including myotonia congenita, dystrophia
myotonica, cystic fibrosis, osteopetrosis, and epilepsy [ 3 ]. The activation of Cl
channels has been found to be responsible for several diseases. There is growing
evidence that the progression of glioma in the brain and the growth of the malaria-
parasite in the red blood cells may be mediated through Cl channel activation
[ 4 - 8 ]. Thus, the study of structure, function, and blockers of Cl channels seems to
be of paramount importance. This article presents a review on all such aspects of
this important class of ion channels.

ions, T-cell activation, and pancreatic b

2 Classification of Cl Channels

Chloride ion channels have been classified according to their gating mechanisms,
which may 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 as CLC chloride channels, cystic
fibrosis transmembrane conductance regulator (CFTR), Ca 2+ -activated Cl
channels (CaCC channels), and ligand-gated Cl channels, respectively. Although
the Cl channels can also be activated by an increase in cell volume, extracellular
acidification, the degree of phosphorylation, and the binding of ATP, only CLC,
CFTR, and

-aminobutyric acid (GABA)-activated (a ligand-gated) Cl channels
have been well recognized [ 9 ]. However, a new class of Cl channels, known as
chloride intracellular channels (CLICs), has also been reported [ 10 , 11 ]. CLICs
have been found to be widely expressed in different intracellular compartments,

g