Scientists May Have Unlocked Function of Mysterious Structure Found on Neurons in the Brain

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Unusual clusters on nerve cells are calcium-signaling “hotspots” that trigger gene transcription, enabling nerve cells to produce essential proteins.

For 30 years, mystical clusters of proteins discovered on the cell body of nerve cells in the hippocampus, a part of the brain, both interested and baffled James Trimmer.

Now, the prominent teacher of physiology and membrane biology at the UC Davis School of Medicine might lastly have a response. In a brand-new research study released in PNAS, Trimmer and his coworkers expose these protein clusters are calcium signaling “hotspots” in the nerve cell that play an essential function in triggering gene transcription.

Transcription enables parts of the nerve cell’s DNA to be “transcribed” into hairs of RNA that are then utilized to develop the proteins required by the cell.

Structures discovered in lots of animals

Trimmer’s laboratory research studies the enigmatic clusters in mice, however they exist in invertebrates and all vertebrates– consisting of human beings. Trimmer approximates that there can be 50 to 100 of these big clusters on a single nerve cell.

He and his coworkers understood that the clusters are formed by a protein that passes potassium ions through membranes (a potassium channel). They likewise understood these clusters include a specific kind of calcium channel. Calcium channels permit calcium to go into cells, where it sets off a range of physiological reactions depending upon the kind of cell.

Researchers in the Trimmer Lab at the UC Davis School of Medicine have actually found that mystical clusters of proteins discovered on nerve cells are calcium-signaling “hotspots” that trigger gene transcription, enabling nerve cells to produce essential proteins. The discovery might assist form brand-new research study into the function of the “hotspots” in brain function and possibly cause brand-new classes of rehabs.

“The presence of these clusters in neurons is highly conserved,” Trimmer stated. Highly saved functions are fairly the same through evolutionary timescales, recommending they have a crucial practical home in these really various kinds of animals.

The hippocampus, one area of the brain where the clusters are discovered on nerve cells, plays a significant function in knowing and memory. Researchers understood that disturbance to these clusters– for instance, from hereditary anomalies in the potassium channel– leads to extreme neurological conditions. But it was unclear 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 stated.

“A lot of research has focused on calcium signaling in dendrites. Now we understand much more about the significance of signaling at these specific sites on the cell body of the neuron.”– Nicholas C. Vierra

Experiment flooded calcium channels with “decoys”

The experiment that exposed the function of the neuronal clusters was created by Nicholas C. Vierra, a postdoctoral scientist in Trimmer’s laboratory and lead author for the research study.

“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 stated.

For their experiment, the scientists basically “tricked” the calcium channels at these clusters by flooding the nerve cells with decoy potassium channel pieces. When the calcium channels got onto the decoys rather of the genuine potassium channels, they fell away from the clusters.

As an outcome, the procedure referred to as excitation-transcription coupling, which connects modifications in neuronal electrical activity to modifications in gene expression, was suspended.

“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 stated. “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 brand-new opportunities of research study.

“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,” statedVierra “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,” stated Trimmer.

Reference: “Regulation of neuronal excitation– transcription coupling by Kv2.1-induced clustering of somatic L-type Ca 2+ channels at ER-PM junctions” by Nicholas C. Vierra, Samantha C. O’Dwyer, Collin Matsumoto, L. Fernando Santana and James S. Trimmer, 8 November 2021, Proceedings of the National Academy of Sciences
DOI: 10.1073/ pnas.2110094118

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

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