Frequently
Questioned Answers (1)
1. Ion
Channels
1.1.
How does the chemical environment differ between the inside of a cell and the
outside?
Most
substances are present at different concentrations inside and outside the
cell. Potassium ions are much more concentrated inside the cell, sodium
ions are much more concentrated outside the cell, and so on. Over the long
term, these differences are maintained by energy-consuming pumps, conceptually
similar to the pumps that compensate for air leaks from pressurized aircraft.
1.2.
Do the chemical differences balance out electrically, or is there an electrical
potential difference between the inside and outside of the cell?
The
net effect of the various ion imbalances is typically to leave the inside of the
cell about 90 millivolts (mv) negative with respect to the outside.
Patterned changes in this transmembrane voltage are the basis for the
unique properties of nerve and muscle cells.
1.3.
What is an ion channel?
The
cell membrane is bridged by pores, each of which at any given time is either
open or closed, and each of which, when open, allows specific ions (sodium,
potassium, calcium, or chloride) to move into (or out of) the cell. These
pores are called ion channels.
Ion
channels are voltage-gated, meaning that other things being equal, a
channel will be open when, and only when, the transmembrane voltage is within a
specific range. There are a few dozen sorts of channels, varying with
respect to which ions they pass, the voltage range at which they are open, their
speed of opening and closing, and their sensitivity to other factors
(temperature, pH, ion concentrations, and so on).
The
charges carried by ions moving through channels cause the transmembrane voltage
to change, so opening a channel begins a process that will inevitably lead to
the closing of the channel. Along the way, the changing transmembrane
voltage may trigger the opening or closing of other channels as well.
1.4.
How might an ion channel malfunction?
Channels
sometimes fail to open when they should, and sometimes they fail to close when
they should.
2. Action Potentials
2.1.
What is an action potential?
The
normal transmembrane voltage difference is known as the resting potential.
Nerve and cardiac cells can exhibit a stylized sequence of ion-channel opening
and closing in which a sodium channel opens, allowing a rapid inward flow of
sodium ions, changing the cell's internal voltage from about -90 mv to
about +20 mv. This change in voltage causes the sodium channel to
begin closing itself, but the same voltage change causes other channels (mainly
potassium channels) to open, allowing a transient outward flow of potassium ions
that gradually reduces the transmembrane voltage back to -90 mv, a few
hundred milliseconds after the process started. Each such complete
excursion is called an action potential (AP);
an idealized example (from Netter FH, The CIBA Collection of Medical
Illustrations: Heart (Summit, NJ: CIBA
Pharmaceutical Company, 1969), page 48) looks like
The
upward change in transmembrane voltage (from -90 mv to +20 mv) is
called depolarization, while the
downward change back towards -90 mv is called repolarization.
2.2.
Why don't the depolarizing channels re-open as soon as the repolarizing flux has
moved the transmembrane potential back into the range in which the depolarizing
channels are normally open?
After
closing, a channel is for a certain time incapable of reopening.
2.3.
Why does one action potential follow another?
In
some cells (including most cells of the heart), there is no true resting
potential. After an action potential, the voltage level of the inside of
the cell does not rest at -90 mv. Instead, it gradually rises,
leading to the voltage-triggered opening of the depolarizing channels and the
beginning of another action potential. The capacity for this sort of
spontaneous depolarization (and therefore spontaneous initiation of action
potentials) is known as automaticity.
In
cells demonstrating automaticity, the rate of spontaneous depolarization is to
an extent characteristic of the particular cell, but external
factors (temperature, pH, and so on) can affect the rate within certain limits.
2.4.
How can malfunctioning ion channels affect the action potential?
If
depolarizing channels fail to open, or if repolarizing channels fail to close
appropriately, then development of an action potential can be prevented from
occurring at all.
If
depolarizing channels fail to close appropriately, or if repolarizing channels
fail to open, then the action potential can be prolonged. During a
sufficiently prolonged repolarization phase, some depolarizing channels may
recover their ability to open. If they do open, the transmembrane voltage
may rise again (before having ever quite returned to the resting potential) in
what is known as an early afterdepolarization (EAD), which sometimes
looks like this:
(From
Burashnikov A. and Antzelevitch C, Prominent IKs
in epicardium and endocardium contributes to development of transmural
dispersion of repolarization but protects against development of early
depolarizations, J Cardiovasc Electrophysiol
13(2), page 174)
2.5.
Do all cardiac cells have the same mix of ion channels, and thus the same sort
of action potentials?
No.
Some kinds of ion channels are present on all nerve and muscle cells, but others
are present on only some kinds of cells. Even within the muscle cells of
the ventricles, there are at least three different cell populations, as
characterized by their mix of types of ion channels. This figure (courtesy
of Dr. Vladislav V. Nesterenko, from "Drug-induced
torsade de pointes and implications for drug development," by Marek Malik, Charles Antzelevitch,
Michael Sanguinetti, Dan M. Roden, Lou Cantilena, Jeremy N. Ruskin, Silvia G. Priori, Raymond J. Lipicky, and me
(Journal of Cardiovascular Electrophysiology
15(4): 475-495 (2004)
shows
the relation between the action potential in
three different (simulated) canine ventricular myocytes, with parallel displays
of the currents through the most important of the contributing ion channels,
where Ito is the transient outward K+ current; ICaL
is the L-type Ca++ current; INa is the sodium
current (the early sodium current is not seen in the figure because its initial
peak is so much larger than any of the other peaks shown [typical peak of
200 pA/pF]); INaCa is the Na+ / Ca++
exchange current; IKr is the rapid delayed-rectifier K+
current; IKs is the slow delayed-rectifier K+
current; ICl(Ca) is a transient outward Cl-
current, activated by intracellular Ca++; IK1 is
the inward rectifier K+ current; and INaK is the
sodium-potassium exchange (the “sodium pump”). The action potentials
differ in shape and duration from cell type to cell type, and this is because of
the differences in channel activity.
The paper provides a fuller explanation.
3. Cell-Cell Interactions
3.1.
How can one cell's electrical activity affect the electrical activity of another
cell?
Some
adjacent cells are directly coupled, so that ion flows in either cell lead to
more-or-less immediate changes in the transmembrane potential of the
other. Even where these specialized connections are not present, adjacent
cells' transmembrane potentials tend to approach each other through capacitative
and other forms of electrical coupling. In particular, the occurrence of
an action potential in one cell is likely to trigger action potentials in
adjacent cells.
4. Electrical Development of Each Heartbeat
4.1.
How do the action potentials of the various cardiac cells combine to produce a
normal heartbeat?
Of
all the cells in the heart, those of the sinoatrial node (the S-A node)
normally have the most rapid rate of spontaneous depolarization.
Action potentials in the sinoatrial node trigger action potentials in the atrial
muscle cells and in bands of specially-connected cells leading to the
atrioventricular node (the A-V node).
The action potentials triggered there are propagated in turn through the conduction
system that includes the specially-connected Bundle of His, right and left
bundle branches, and Purkinje fibers. Finally, the action potentials in
the Purkinje fibers trigger action potentials in the ventricular muscle cells.
In
the atrial and ventricular muscle cells, the electrical action potential is
associated with a mechanical cycle of contraction and relaxation.
Throughout
this process, even though all of the cardiac cells mentioned are capable of
spontaneous depolarization, spontaneous depolarization does not proceed to the
point of triggering action potentials in cells other than those of the S-A
node. This is because spontaneous depolarization in these other cells is
so slow that the chain of action potentials started in the S-A node for each
normal beat gets to each of the other cells before that other cell has got
around to triggering its own action potential.
4.2.
What can go wrong with this process?
For
present purposes, cardiac electrical disease can be classified as follows:
The cells of the S-A node can sustain a decrease in their
rate of spontaneous depolarization, or even lose their automaticity
altogether. The heart will then be dependent upon impulses generated by
other cells, and the resulting heart rate may be so slow as to be
dysfunctional. Similarly, the A-V node or conduction system can fail, so
that some or all of the impulses started in the S-A node are lost, leaving the
heart beyond this point dependent upon spontaneous depolarization of slower
pacemakers.
One or more cells elsewhere in the heart can develop
rates of spontaneous depolarization faster than those of the S-A node, so that
these cells trigger action potentials in themselves and in adjacent cells,
independent of the S-A node. The resulting cardiac activity (a triggered
arrhythmia) may be merely less organized and less efficient than the normal
one, or it may (especially if it is very rapid) be totally ineffective.
In various ways, most simply by development of an island
of electrically inert and nonconductive tissue surrounded by normal cells, the
heart can acquire a loop of tissue around which a chain of action potentials
can trigger itself indefinitely, with – in the worst case – each cell
triggered by the previous one as soon as its depolarizing channels could
possibly reopen. The triggering action potentials need not be full-scale
action potentials; early afterdepolarizations may be sufficient. Cells
adjacent to the loop can be triggered too, and the resulting cardiac activity
(a reentrant arrhythmia) is often
dysfunctional.
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