Biomedical Engineering Reference
In-Depth Information
QSTR
Quantitative structure-toxicity relationship
RASMC
Rat aortic smooth muscle cells
WHIM
Weighted holistic invariant molecular descriptors
1
Introduction
Ion channels are part of cell membranes. They are pore-forming proteins embedded
in the membranes that surround all biological cells. Depending on the type of
channel, they regulate the flow of specific ions such as sodium, potassium, calcium,
or chloride by means of voltage gradient across the membrane [
1
]. Of the different
approaches to categorize ion channels, the most acceptable one appears to be the
way the ion channels are regulated. Accordingly, they can be divided into three
main groups as (a) the voltage-gated channels (e.g., the sodium and potassium
channels of the nerve axons and nerve terminals), (b) the extracellular ligand-
activated channels (e.g., neurotransmitter regulated channels i.e., GABA and gly-
cine receptor channels) and (c) the intracellular ligand-gated ion channels (e.g.,
the cystic fibrosis transmembrane conductance regulator - CFTR, ATP-binding
Cassette - ABC superfamily and ion channels of sense perception). In all living
organisms, potassium channels are the most widely distributed and control diverse
cellular functions, which include shaping action potentials in excitable cells (e.g.,
neurons and cardiac muscle) and secretion of hormones (e.g., insulin release from
beta-cells in the pancreas) [
2
-
4
]. They are formed from four protein subunits, either
a homotetramer complex of C
4
symmetry or a heterotetrameric complex of pseudo
C
4
symmetry, with a central ion conducting pore [
5
-
8
]. Depending upon the
function, the potassium channels may be put in four major classes [
1
,
9
] as (a)
calcium-activated potassium channel, (b) inwardly rectifying potassium channel
(
K
ir
or IRK), (c) tandem pore domain potassium channel and (d) voltage-gated
potassium channels. As the name indicates, the calcium-activated potassium chan-
nels open in response to Ca
2+
and/or other signaling ligands. The blocking of these
channels increases intracellular calcium. The
K
ir
channel passes positive current
into the cell and play important role in regulating neuronal activity via establishing
the resting membrane potentials of the cell. They are found in variety of cells,
which include cardiac, kidney, leukocytes, neurons and endothelial. The tandem
pore domain potassium channels are two-pore-domain potassium channels. They
are also known as “leak channels” [
10
] and set the negative membrane potential
of neuron. When open, they allow potassium ions to cross the membrane very fast.
These channels are regulated via G-proteins, oxygen tension, pH, etc. The voltage-
gated potassium channels are transmembrane potassium channels sensitive to
voltage changes in the cell's membrane. During action potentials, they play a
vital role in returning the depolarized cell to a resting state.
Ion channels play important role in a variety of diseases ranging from the
cardiovascular nervous, immune and endocrine systems to the cancer metastasis
[
11
-
16
]. Also, number of chemical entities as well as genetic disorders can disrupt
