Function of mysterious structure found on neurons

Date:
November 11, 2021
Source:
University of California - Davis Health
Summary:
Researchers have discovered that mysterious clusters of proteins
found on neurons are calcium-signaling 'hotspots' that activate gene
transcription, allowing neurons to produce crucial proteins. The
discovery may help shape new research into the role of the
hotspots in brain function and potentially lead to new classes
of therapeutics.



FULL STORY ==========================================================================
For 30 years, mysterious clusters of proteins found on the cell body
of neurons in the hippocampus, a part of the brain, both intrigued and
baffled James Trimmer.


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Now, the distinguished professor of physiology and membrane biology
at the UC Davis School of Medicine may finally have an answer. In a
new study published in PNAS, Trimmer and his colleagues reveal these
protein clusters are calcium signaling "hotspots" in the neuron that
play a crucial role in activating gene transcription.

Transcription allows portions of the neuron's DNA to be "transcribed"
into strands of RNA that are then used to create the proteins needed by
the cell.

Structures found in many animals Trimmer's lab studies the enigmatic
clusters in mice, but they exist in invertebrates and all vertebrates -- including humans. Trimmer estimates that there can be 50 to 100 of these
large clusters on a single neuron.

He and his colleagues knew that the clusters are formed by a protein that passes potassium ions through membranes (a potassium channel). They also
knew these clusters contain a particular type of calcium channel. Calcium channels allow calcium to enter cells, where it triggers a variety of physiological responses depending on the type of cell.



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"The presence of these clusters in neurons is highly conserved,"
Trimmer said.

Highly conserved features are relatively unchanged through evolutionary timescales, suggesting they have an important functional property in
these very different types of animals.

The hippocampus, one region of the brain where the clusters are found
on neurons, plays a major role in learning and memory. Researchers knew
that disruption to these clusters -- for example, from genetic mutations
in the potassium channel -- results in severe neurological disorders. But
it was not clear why.

"We have known the function of other types of ion channel clusters,
for example those at synapses, for a long time. However, there was no
known role that these much larger structures on the cell body played in
the physiology of the neuron," Trimmer said.

Experiment flooded calcium channels with "decoys" The experiment that
revealed the function of the neuronal clusters was designed by Nicholas
C. Vierra, a postdoctoral researcher in Trimmer's lab and lead author
for the study.



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"We developed an approach that let us uncouple the calcium channel from
the potassium channel clusters in neurons. A key finding was that this treatment blocked calcium-triggered gene expression. This suggests that
the calcium channel-potassium channel partnership at these clusters is important for neuronal function," Vierra said.

For their experiment, the researchers essentially "tricked" the calcium channels at these clusters by flooding the neurons with decoy potassium
channel fragments. When the calcium channels grabbed onto the decoys
instead of the real potassium channels, they fell away from the clusters.

As a result, the process known as excitation-transcription coupling,
which links changes in neuronal electrical activity to changes in gene expression, was inactivated.

"There are a lot of different calcium channels, but the particular type
of calcium channel found at these clusters is necessary for converting
changes in electrical activity to changes in gene expression," Trimmer
said. "We found that if you interfere with the calcium-signaling
proteins located at these unusual clusters, you basically eliminate excitation-transcription coupling,which is critical for learning, memory,
and other forms of neuronal plasticity." Trimmer and Vierra hope their findings will open new avenues of research.

"A lot of research has focused on calcium signaling in dendrites --
the sites where neurons receive signals from other neurons. Calcium
signaling in the cell body of neurons has received less attention,"
said Vierra. "Now we understand much more about the significance of
signaling at these specific sites on the cell body of the neuron."
"We are only at the beginning of understanding the significance of this signaling, but these new results may provide information that could shape
new research into its role in brain function, and perhaps eventually
into the development of new classes of therapeutics," said Trimmer.

Additional authors on the study include Samantha C. O'Dwyer, Collin
Matsumoto and L. Fernando Santana, Department of Physiology and Membrane Biology, UC Davis School of Medicine.

This research was funded by awards from the National Institutes of Health.

========================================================================== Story Source: Materials provided by
University_of_California_-_Davis_Health. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Nicholas C. Vierra, Samantha C. O'Dwyer, Collin Matsumoto,
L. Fernando
Santana, James S. Trimmer. Regulation of neuronal excitation-
transcription coupling by Kv2.1-induced clustering of somatic
L-type Ca2 channels at ER-PM junctions. Proceedings of the
National Academy of Sciences, 2021; 118 (46): e2110094118 DOI:
10.1073/pnas.2110094118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211111080412.htm

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