Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

622 Chapter 11: Membrane Transport of Small Molecules and the Electrical Properties of Membranes
N
(A)
SIDE
VIEW
TOP
VIEW
selectivity
filter
+
S4 helix
central channel
voltage sensors
+
voltage sensors
pore
central channel
CYTOSOL
lipid
bilayer
(C)
+
inactivation gate
lateral
portal
+
lateral
portal
C
CYTOSOL
Figure 11–29 Structural models of
voltage-gated Na + channels. (A) The
channel in animal cells is built from a
single polypeptide chain that contains
four homologous domains. Each domain
contains two transmembrane α helices
(green) that surround the central ionconducting
pore. They are separated by
sequences (blue) that form the selectivity
filter. Four α additional helices (gray
and red) in each domain constitute the
voltage sensor. The S4 helices (red) are
unique in that they contain an abundance
of positively charged arginines. An
inactivation gate that is part of a flexible
loop connecting the third and fourth
domains acts as a plug that obstructs the
pore in the channel’s inactivated state, as
shown in Figure 11–30. (B) Side and top
views of a homologous bacterial channel
protein showing its arrangement within the
membrane. (C) A cross section of the pore
domain of the channel shown in (B) shows
lateral portals, through which the central
cavity is accessible from the hydrophobic
core of the lipid bilayer. In the crystals, lipid
acyl chains were found to intrude into the
pore. These lateral portals are large enough
to allow entry of small, hydrophobic, poreblocking
drugs that are commonly used as
anesthetics and block ion conductance.
(PDB code: 3RVZ.)
(B)
Panel 11–1, p. 616). At this point, when the net electrochemical driving force for
the flow of Na + is almost zero, the cell would come to a new resting state, with all of
its Na + channels permanently open, if the open conformation of the channel were
stable. Two mechanisms act in concert to save the cell from such a permanent
electrical spasm: the Na + channels automatically inactivate and voltage-gated K +
channels open to restore the membrane potential to its initial negative value.
The Na + channel is built from a single polypeptide chain that contains four
structurally very similar domains. MBoC6 n11.555/11.30
It is thought that these domains evolved by
gene duplication followed by fusion into a single large gene (Figure 11–29A). In
bacteria, in fact, the Na + channel is a tetramer of four identical polypeptide chains,
supporting this evolutionary idea.
Each domain contributes to the central channel, which is very similar to the K +
channel. Each domain also contains a voltage sensor that is characterized by an
unusual transmembrane helix, S4, that contains many positively charged amino
acids. As the membrane depolarizes, the S4 helices experience an electrostatic
pulling force that attracts them to the now negatively charged extracellular side of
the plasma membrane. The resulting conformational change opens the channel.
The structure of a bacterial voltage-gated Na + channel provides insights how the
structural elements are arranged in the membrane (Figure 11–29B and C).
The Na + channels also have an automatic inactivating mechanism, which
causes the channels to reclose rapidly even though the membrane is still depolarized
(see Figure 11–30). The Na + channels remain in this inactivated state, unable
to reopen, until after the membrane potential has returned to its initial negative
value. The time necessary for a sufficient number of Na + channels to recover from
inactivation to support a new action potential, termed the refractory period, limits