Biomedical Engineering Reference
In-Depth Information
Abbreviations
CCBs Ca
2+
channel blockers
DRG Dorsal root ganglion
GFA Genetic function approximation
LCC L-type Ca
2+
channel
NCC N-type Ca
2+
channel
P/QCC P- and Q-type Ca
2+
channel
QSAR Quantitative structure-activity relationship
RCC R-type Ca
2+
channel
TCC T-type Ca
2+
channel
VGCCs Voltage-gated Ca
2+
channels
1
Introduction
N-type Ca
2+
channels (NCCs) are associated with central and peripheral neurons,
being located on the presynaptic nerve terminals. These channels regulate the Ca
2+
flux subserving depolarization-evoked release of neurotransmitter from presynaptic
endings. At the presynaptic nerve terminal, voltage-gated Ca
2+
channels (VGCCs)
open in response to action potentials to allow an influx of Ca
2+
ions. The influx is a
graded process varying in a linear manner with the frequency of action potentials.
These in turn lead to release of various neurotransmitters that diffuse across the
synaptic cleft to the postsynaptic membrane and binds to their specific receptors.
Neurotransmission in the central and peripheral nervous system is mainly
controlled by NCCs. NCC was identified as promising and selective druggable
target for the treatment of pain because it mediates the neurotransmission of pain
signals in the spinal cord. It is also well known that NCCs play an important role in
stroke disease in which modification in the intracellular Ca
2+
signaling during
neuronal ischemia could be inhibited by blocking NCC and thereby preventing
neuronal death [
1
,
2
]. Ligand-gated NCCs open or close in response to the binding
of the ligand or small signaling molecule such as Prialt (synthetic version of omega-
conotoxin-GVIA), an FDA-approved drug for chronic pain treatment. Prialt is a
potent and selective NCC blocker. Some drugs are known to stabilize or destabilize
the NCC open state. Ligand plugging at the ligand sensing residues of NCC will
stabilize/destabilize its open state gating mechanism and therefore could play an
important role in the ion channelopathies [
3
-
16
].
Neuronal VGCCs are integral multimeric protein complexes found in presynaptic
membrane of neurons that mediate the selective passage of specific ions or
molecules across a cell membrane. Free intracellular Ca
2+
is the most common
signal transduction element in cells [
17
]. An electrochemical gradient exists between
an extracellular and intracellular (cytoplasmic) Ca
2+
concentrations and further these
enter the cytosol either through plasma membrane VGCCs or is released from the
intracellular pools. These channels are important in a diverse range of physiological
processes, including signal transmission in the nervous system, sensory perception,
