Biomedical Engineering Reference
In-Depth Information
13.4
VOLTAGE-GATED SODIUM CHANNELS
13.4.1 S
TRUCTURE
AND
M
OLECULAR
B
IOLOGY
OF
V
OLTAGE
-G
ATED
S
ODIUM
C
HANNELS
Functionally, Na
v
s are closed at the resting membrane potential and open when the membrane
becomes depolarized, activation requiring membrane potentials of −70 to −30 mV, with some varia-
tion between different Na
v
types. Most Na
v
s inactivate within ~1-10 ms in the presence of sustained
depolarization. In certain types of neurons, a more persistent Na
v
current with slow inactivation has
also been identii ed.
At the molecular level, Na
v
s are composed of a large (~2000 amino acid residues)
α
-subunit,
which is structurally similar to the
α
1
-subunit of Ca
v
s, and forms the ion conducting pore
(Figure 13.7A). The high selectivity for Na
+
over K
+
is due to the composition of the ion selectiv-
ity i lter, which consists of two rings of amino acids with each of the four homologous domains
contributing one amino acid to each ring: outer ring with Glu-Glu-Asp-Asp and inner ring with
Asp-Glu-Lys-Ala. The rapid inactivation of most Na
v
s is explained by the cytoplasmic domain
III-IV linker (Figure 13.9B h motiv), which functions as a “hinged lid,” that simply swings in to
occlude the intracellular mouth of the pore.
Nine different Na
v
-subunits (Na
v
1.1-Na
v
1.9) have been cloned and all these display >50%
amino acid identity with each other, so they compose one subfamily. The Na
v
1 family has most
likely arisen from a singe ancestral gene and that their present diversity rel ects gene duplication
events and chromosomal rearrangements occurring late in evolution.
By analogy to the Ca
v
s, functional Na
v
s can be formed from expression of
α
α
-subunits alone
although native Na
v
s are protein complexes composed by
α
-subunits and auxiliary subunits. Only
a single class of auxiliary Na
v
subunits (
β
-subunits) has been identii ed.
β
-Subunits are composed
of a large extracellular part, through which it interacts with the
-subunit (Figure 13.7B) and a
small C-terminal portion consisting of a single TM segment. The function of the
α
-subunits can
be divided into: (1) modulation of the functional properties of Na
v
s, (2) enhancement of membrane
expression, and (3) mediating interactions between Na
v
s and extracellular matrix proteins as well as
various signal transduction molecules.
β
13.4.2 P
HYSIOLOGICAL
R
OLES
OF
V
OLTAGE
-G
ATED
S
ODIUM
C
HANNELS
The biological importance of Na
v
s relies on their ability to cause depolarization of cell membranes.
Most of the Na
v
-subunits are capable of detecting even very small increases in membrane poten-
tial and this makes the Na
v
s activate, and subsequently inactivate, on a ms time scale. This combina-
tion of high sensitivity toward depolarization and very rapid gating kinetics makes Na
v
s perfect for
initiating and conducting action potentials.
Na
v
1.1, Na
v
1.2, Na
v
1.3, or Na
v
1.6 subunits are expressed in virtually all neurons within the CNS,
in particular, at the base and along the entire length of the axon. When an excitatory synaptic signal
(e.g. glutamate, released by a neighboring neuron, acting on AMPA receptors, see Chapter 15) is
received, this generates a small depolarization of the neuronal membrane in the dendrites and cell
body. This rather modest depolarization is sufi cient for activating Na
v
s at the initial segment of the
axon, leading to the generation of an AP. Once the AP reaches the nerve terminal, this will activate
Ca
v
s, leading to release of neurotransmitter. The importance of these Na
v
s for AP initiation and
conduction is also highlighted by the fact that point mutations in the genes encoding Na
v
1.1, Na
v
1.2,
and Na
v
1.3, which alter their functional properties, have been linked to certain forms of epilepsy.
Dorsal root ganglion (DRG) neurons are important for transmitting sensory signals, including
pain, from the periphery to the CNS. Sensory stimulation leads to generation and conduction of
action potentials in DRG neurons and these APs are mediated by Na
v
s. Na
v
s of DRG neurons contain
the Na
v
1.7, Na
v
1.8, and Na
v
1.9 subunits, which are almost exclusively expressed in these neurons. It
has also been shown that expression of these
α
α
-subunits is altered in a complex fashion in animal
