Biomedical Engineering Reference
In-Depth Information
Table 1 VGSC
-subunit subtypes
VGSC
a
-subunit nomenclature Gene Tetrodotoxin sensitivity Major tissue expression
Na
v
1.1
SCN1A
TTXs CNS, PNS
Na
v
1.2
SCN2A
TTXs CNS, PNS
Na
v
1.3
SCN3A
TTXs CNS, PNS
Na
v
1.4
SCN4A
TTXs Skeletal muscle
Na
v
1.5
SCN5A
TTXr Heart
Na
v
1.6
SCN8A
TTXs CNS, PNS
Na
v
1.7
SCN9A
TTXs PNS (SNS and PAs)
Na
v
1.8
SCN10A
TTXr PNS (PAs)
Na
v
1.9
SCN11A
TTXr PNS (PAs)
Na
x
SCN6/7A
Non-functional Glia
CNS
central nervous system;
PNS
peripheral nervous system;
PAs
primary afferent neurons;
SNS
sensory nervous system
a
whereas
SCN9A
-
SCN11A
genes codify proteins Na
v
1.6-Na
v
1.9 (Table
1
). The
expression of the various subtypes is both cell and tissue specific, and in some
cases it changes during development [
4
]. Na
v
1.6 is the main subunit expressed in
mammalian brain during adulthood, but also Na
v
1.1 and Na
v
1.2 are present in
axons and neuronal somata. Na
v
1.3 subunits are expressed primarily in embryonic
neurons in rodents, although they can be found in adult human brain for an extended
period after embryogenesis. Na
v
1.4 subunits are the main VGSC subtype expressed
in the skeletal muscle, whereas Na
v
1.5 subunits are located in cardiac muscle.
Finally, proteins Na
v
1.7-Na
v
1.9 are present in peripheral primary sensory afferents.
The nine
-subunits have been classified according to the dose of tetrodotoxin that
blocks them. Namely, Na
v
1.1-Na
v
1.4, Na
v
1.6 and Na
v
1.7 are tetrodotoxin-sensi-
tive (TTXs) as they are inhibited by nanomolar concentration of the toxin; con-
versely, Na
v
1.5, Na
v
1.8 and Na
v
1.9 are tetrodotoxin-resistant (TTXr) as they
require much higher concentrations to be blocked.
a
2.4 Diseases Related to VGSCs
Sodium channelopathies are inherited disorders caused by mutations in genes
encoding VGSCs, which have proven to be particularly interesting as they provide
significant insights into the physiological function of each VGSC and help
clarifying molecular processes underlying normal and malfunctioning electrical
excitability [
18
,
19
]. Mutations in VGSC also provide medicinal chemists with
useful cues, which could be treasured for the identification of selective modulators
for different VGSC isoforms, as each channelopathy involves specific alterations
either in the expression or in the function of individual channels. On the contrary,
the present scenario urge scientists to search for specific blockers, since nonselec-
tive drugs induce undesired side effects [
20
]. Mutated VGSC genes have been
found both in the central (CNS) and in the peripheral (PNS) nervous systems as well
