(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have discovered the
mechanism that facilitates how two ion channels collaborate in the
control of electrical signals in the brain. The investigators showed
that the channels were anchored by a third protein at key locations
on the nerve cell surface, allowing them to work together to set
the timing and pattern of nerve impulses. They also found that this
channel partnership mechanism is present in all vertebrates, but
is lacking in invertebrates, suggesting that the coupling of these
channels may be essential for the higher abilities of vertebrate
brains. The elucidation of this novel interaction should aid efforts
to develop new treatments for epileptic seizures, pain, and abnormal
muscle movements. They report their findings in the cover article
of the March 8 issue of the Journal of Neuroscience.
and potassium are salt molecules (or ions) found throughout the
body. Cells pump extra potassium into their interiors, and pump
extra sodium out to the surrounding fluid. Electrical impulses in
neurons are created when these ions are allowed to return to their
original locations by passing rapidly through channels in nerve
cells’ outer membranes. Nerve cells possess wire-like extensions,
called axons, which initiate these impulses and carry them from
one cell to the next.
Penn’s Edward Cooper, MD, PhD, Assistant
Professor of Neurology, and colleagues, zeroed in on two key regions
of nerve axons - the initial segment, where each impulse starts,
and the nodes of Ranvier, outlying stations spaced along the axon
where the impulse receives an essential electrical boost - to look
for the anchoring. Nerve impulses begin after exciting inputs are
received by the nerve cell - either from the environment or from
other nerve cells in the body. Once adequate input signals have
accrued, the movement of sodium into the cell will start a nerve
impulse at the axon initial segment. In response to this activity,
potassium channels then open, permitting the outward movement of
“The sodium channel opening at the beginning of a nerve impulse
is like releasing a compressed spring,” Cooper explains. “Without
other influences, there is a tendency to keep reverberating, leading
to additional, unwanted nerve impulses.”
Potassium channels have a calming influence on the nerve. “Potassium
channels work like shock absorbers, holding back sodium channel
activity for a period after each nerve impulse,” Cooper continues.
Indeed, some patients have mutations in potassium channels that
decrease this control, causing excessive nerve firing manifested
as epileptic seizures and uncontrolled muscle movements called myokymia
The efficient and speedy passage of nerve impulses along axons is
aided by the presence of an insulating cover, known as myelin, which
maintains the electrical activity along the entire length of the
axon. The nerve impulse is able to skip across the unmyelinated
regions of the axon at the nodes of Ranvier, with the help of sodium
and potassium channels.
“Each nerve impulse receives a huge boost from the influx
of additional sodium ions at these nodes, which allows the signal
to be propagated to the next myelinated region of the axon,”
In a series of chemical tests on the potassium channels located
on the axon initial segment and the nodes of Ranvier, the research
team was able to identify a molecular motif that allows both channel
types to link to a protein called ankyrin-G. Ankyrin-G, in turn,
binds tightly to the nerve cell’s cytoskeleton, ensuring the
channels’ stabilization at the initial segment. The chemical
motif identified in the potassium channels was nearly identical
to that previously discovered in sodium channels, revealing that
the potassium and sodium channels link to the ankyrin-G protein
in a similar manner.
“The ankyrin-G-interaction with potassium and sodium channels
establishes a unique domain of the cell for initiating the nerve
impulse and for boosting the impulse across the nodes of Ranvier,”
A comparison of several vertebrate and invertebrate channels led
to the discovery that the ankyrin-G interaction is present only
in vertebrate species. The chemical motif present in vertebrates
did not exist in the potassium channels or sodium channels of invertebrates.
This comparison led Cooper and colleagues to realize that the evolutionary
split between vertebrates and invertebrates, as demonstrated by
this difference in the organization of sodium and potassium channels
along neurons, occurred during a similar period in evolutionary
history as the appearance of myelin.
“Myelination and the coupling of axonal sodium and potassium
channels are fundamental improvements in the nervous system, and
these changes are probably necessary for the vertebrate ‘life-style’,”
explains Cooper. “You can only be large and fast-moving if
you have a nerve impulse mechanism that is both rapid and highly
By understanding the relationship between potassium and sodium channels,
Cooper and colleagues are working to create new treatments for neurological
diseases based on reestablishing the type of nerve-cell impulse
control seen in unaffected individuals. In fact, a new drug that
acts by increasing the openings of these potassium channels is now
undergoing U.S. and international trials for epilepsy, and such
agents are also being developed for other neurological and psychiatric
Study co-authors are Zongming Pan, Tingching Kao, Zsolt Horvath,
Julia Lemos, Jai-Yoon Sul, Stephen D. Cranstoun, and Steven S. Scherer,
all from Penn, as well as Vann Bennett from Duke University and
the Howard Hughes Medical Institute. This research was funded in
part by the National Institutes of Health, the Whitaker Foundation,
and the University of Pennsylvania McCabe Foundation.
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