July 02, 1999
Protein Studies Reveal Sophisticated Control
of Nerve Communication
With their discovery of a curious brain protein, named for a Chinese
breakfast noodle, a team of HHMI investigators have provided a new
understanding of just how exquisitely nerve cells control the
electrical impulses they use to communicate with one another.
The protein yotiao (pronounced "YOH-tee-ow") anchors itself on the
inner membrane of neurons in the hippocampus, a small brain region
associated with learning and memory. Like other anchoring proteins,
yotiao is an organizer whose purpose is to corral particular enzymes or
other molecules that govern cell functions into specific "compartments"
or pools within a cell. Yotiao itself is somewhat unusual in that it
binds not one but two kinds of enzymes, both of which help regulate
electrical signals that pass from neuron to neuron.
But "the really cool thing about yotiao," explained HHMI
investigator John D. Scott, is that it holds the enzymes right next to
their site of action — a crucial type of receptor known as
N-methyl-D-aspartate (NMDA) receptors. NMDA receptors nestle in the
specific part of the nerve cell membrane where neurons communicate
chemically with each other across a tiny gap known as a synapse. They
are the principal channels through which positively charged calcium
ions stream into the nerve cell. The rapid inflow of calcium and
outflow of another ion, potassium, generates an electrical nerve
signal.
"This is one of the first times, if not the first, that we've seen
an anchor protein that physically attaches not only to signaling
enzymes but also to their receptor," said Scott, whose laboratory is at
the Vollum Institute of Portland's Oregon Health Sciences University.
"That means the receptor has everything it needs absolutely at the
right place, ready for action whenever it needs it.
"We've known that the cell is not just a bag of enzymes floating
around," he continued. "But yotiao tells us that its signaling control
is much, much more sophisticated and precise than we thought."
Scott and other members of his team, including Lorene Langeberg and
Iain Fraser, collaborated with members of HHMI investigator Morgan
Sheng's laboratory at the Massachusetts General Hospital, describe
their findings in the July 2, 1999 issue of the journal
Science.
The story of yotiao's discovery began in the early 1990s, when
Fraser isolated a small piece of DNA. "We had very little idea what it
was," said Scott. But a better picture began to emerge as postdoctoral
researcher Ryan Westphal with help from graduate student Neal Alto
gradually isolated overlapping pieces of DNA, and regions of the
sequence began to look familiar. That recognition led Scott and his
team to their eventual identification of yotiao.
Since the early 1990s, Scott has focused his research on the process
by which chemical signals from outside a cell are transported through
the nerve cell membrane to particular locations within the cell, where
they exert their biological effect. He is particularly interested in
one such signaling pathway that activates an enzyme called
cAMP-dependent protein kinase (PKA), and how nerve cells organize
specialized pools of PKA so that these pools will be ready for instant
use.
As it turns out, PKA is one of the two enzymes that yotiao holds
near the NMDA receptors. Whenever the anchor protein releases it, PKA
stimulates the channels to allow in more calcium ions.
Yotiao's other closely held enzyme, called type 1 protein
phosphatase (PP1), has the opposite effect: it downregulates NMDA
receptors, or slows the flow of ions. Steven Tavalin, an HHMI associate
in Scott's laboratory, has shown that PP1 is also at work even while it
is still bound to yotiao. The net effect, then, of yotiao and its two
enzymes is that calcium is prevented from entering neurons at rest.
That constant blockade may sound curious at first, Scott said, but
he believes it's an important feature of signaling control. "Think of
an electrical signal traveling along a nerve, how rapidly the neuron
needs to fire and then get back to the resting state," he pointed out.
"PP1 helps the neuron reach that resting state quickly so that it is
ready to help you do or think something else almost instantly."
In learning a new skill, for example, nerve cells in the brain's
hippocampus begin to fire off electrical impulses, storing one step of
the instructions after another for later recall. One stimulated neuron
tells the next in line to fire by releasing chemical messengers called
neurotransmitters across the synaptic gap, which serves as a sort of
firewall against short-circuits.
The neurotransmitters — in this case, glutamate and cyclic AMP
— act as on-off switches for the electrical impulses. They bind to
and activate their targets on the receiving neuron, which are none
other than NMDA receptors. Calcium ions flood the cell, and the
corresponding change in electrical state causes that neuron in turn to
fire.
And if neurotransmitters are the switches, said Scott, yotiao's
enzymes PKA and PP1 are the volume controls. Because of their proximity
to the channel, they can instantly enhance or dampen the level of ion
flow to ensure proper firing and rapid recovery.
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