Biomedical Engineering Reference
In-Depth Information
2 Sodium Channels: Their Structure and Functions, Diseases
Related to Na-Channels
2.1 VGSC Structure
VGSCs are a family of membrane proteins forming a pore, through which they
selectively conduct sodium ions inward and outward cell's plasma membranes in
response to variations of membrane potentials [
2
-
4
]. They are composed of a
central
-subunits; the former is endowed with
characteristics, which make the channels fully functional, whereas the latter ones
mediate the linkage of the
a
-subunit and of two auxiliary
b
-subunit to the plasma membrane and influence
biophysical properties of the channels [
5
]. The
a
-subunit is a large polypeptide of
about 1,800 amino acids and of 260 kDa, which consists of four domains (I-IV or
D1-D4), each developed through six
a
-helical transmembrane segments (S1-S6) as
shown in Fig.
1
. Toxin bindings on the external pore, mutational analysis and
parallel studies carried on for voltage-gated potassium channels suggest that the
four S5-S6 linkers, one from each domain, which are designed as P-loops, form the
extracellular portion of the channel, a ring of suitable size and charge that works as
the selectivity filter for sodium ions. There are evidences indicating that each S5-S6
loop contributes to the selectivity pore with a single crucial amino acid (aspartate
from domain I, glutamate from domain II, lysine from domain III, and alanine from
domain IV), all negatively charged. Similar to other ion channels, S6 segments, in
each domain of VGSCs, form the cytoplasmic end of the ion pore. Mutagenesis
studies have shown how local anesthetics (LA) have high affinity for the inactivated
state of VGSCs due to their interaction with critical amino acid residues located on
the inner portion of the pore, on S6 segments of domains I, III, and IV (Fig.
1
)[
6
].
Antiarrythmic and antiepileptic sodium channel blockers also bind to the same site
as LA [
7
,
8
]. The S4 segments, one in each domain of the VGSC heterotetramer,
contain positively charged amino acids regularly spaced along the
a
-helix and
function as voltage sensors. Mutational analysis suggests that upon membrane
depolarization the four S4 segments cross the membrane by an outward rotational
movement and start the gating process by inducing the channel opening [
9
]. Site-
directed antipeptide antibodies indicate that the intracellular loop between domain
III and IV closes the cytoplasmic end of the pore of the VGSC
a
-subunit leading to
the fast-inactivation of the channel (Fig.
1
)[
10
,
11
]. The
C
terminus of the
a
-subunit
contributes to the stabilization of the VGSC inactivated state by influencing fast-
inactivation and by binding interacting proteins [
12
,
13
].
a
-Subunits are transmem-
brane glycoproteins of about 35 kDa, playing an accessory role in VGSC functioning
(Fig.
1
). Four different subtypes have been identified so far (
b
b
1-
b
4), each one
a
b
composed of a single
-Subunits
are endowed with a short cytoplasmic
C
terminus and with a large extracellular
N
terminus, which resemble an immunoglobulin outer domain capable to bind
external proteins and thereby is believed to influence VGSC migration.
-helix stretching through the plasma membrane.
b
-Subunits
