Calcium-signaling “hotspots” on neurons that activate gene transcription allow neurons to produce critical proteins, according to James Trimmer for 30 years, strange clusters of proteins on the cell body of neurons in the hippocampus, a section of the brain, has intrigued and perplexed him.
The distinguished professor of physiology and membrane biology at the University of California, Davis School of Medicine may now have an answer.
In a paper published in PNAS, Trimmer and his team reveal these protein clusters are calcium signaling “hotspots” in the neuron that play a critical role in gene transcription activation. transcription allows parts of the neuron’s DNA to be copied into RNA.
“This is potentially a major discovery,” said Trimmer, who has been studying neurons for more than 40 years. “It’s the first time we’ve seen this and we think it should make a big difference in how we understand neuron physiology.”
Several animals have these structures
The elusive clusters in mice are studied by Trimmer’s lab, but they exist in invertebrates and all vertebrates, including humans. The clusters are made up of a potassium channel that passes ions through membranes.
They also discovered that these clusters include a distinct type of calcium channel. Calcium channels allow calcium to enter cells, where it causes various reactions, including activation of gene transcription.
“Until now we didn’t know anything about calcium channels in these hotspots,” Trimmer said. “We’ve never had the technology to examine this.”
Trimmer’s lab has been studying individual cells in mice brains since 1979. In those early years, they chose a single cell from the hippocampus at random, making a dissociated cell culture.
The one they chose turned out to be a glutamate neuron. Glutamate neurons are responsible for about 50 percent of brain activity, which makes these cells particularly important in understanding the neurological disease or normal function.
Researchers at the UC Davis School of Medicine’s Trimmer Lab have discovered that strange clusters of proteins on neurons are calcium-signaling “hotspots,” which activate gene transcription and allow neurons to generate important proteins.
The finding may help researchers design new studies into the function of “hotspots” in brain activity and potentially lead to new classes of medicines.
The presence of these clusters in neurons is highly conserved, according to Trimmer. The conservation of highly conserved features indicates that they have a critical function in animals with such diverse characteristics.
“This is a major advance in our understanding of how neurons function,” Trimmer said.
Trimmer has been a pioneer in the study of ion channels for decades. He discovered that potassium channels consist of multiple subunits, each with its own role to play in generating currents. His work on this structure was honored by the Gairdner Foundation in 2003.
Trimmer is a member of the National Academy of Sciences, a fellow of the American Association for the Advancement of Science and a former chief scientific officer at Neurogen Corporation, a biotechnology company that he co-founded in 1989. He was also elected to serve as president for The Biophysical Society from 2008-2010.
“We know the function of other kinds of ion channel clusters, such as those found at synapses, for a long time. However, there was no known function for these much larger structures on the cell body in neuron physiology,” Trimmer noted.
A lot of studies have been done on calcium signaling in dendrites. Now, thanks to our understanding of the importance of signaling at these specific locations on the cell body of the neuron, we are better able to understand it.” — Nicholas C. Vierra
Experiment with “simulated” calcium channels to flood the channels.
Nicholas C. Vierra, a postdoctoral researcher in Trimmer’s lab and the study’s lead author, devised the experiment that revealed the role of neuronal clusters.
“We developed a method that separated the calcium channel from the potassium channel cluster,” Vierra said. This finding suggests that the calcium channel-potassium channel connection at these clusters is crucial for neuronal function. “It’s a very elegant experiment,” Trimmer said.
Vierra used his method to identify three calcium channels in the cluster, which he refers to as Cch1a, Cch1b and Cch1c.
He found that neurons with all three channels activated had higher rates of neuronal activity than those containing only one or two channels. Then, Vierra flooded the neurons with calcium to see what would happen to their activity.
“The effect was much more dramatic in those cells that had three channels,” Trimmer said. “In those neurons where fewer channels were activated, the elevation of calcium lasted only a short time.”
For their study, the scientists “tricked” the calcium channels at these clusters by flooding the neurons with decoy potassium channel fragments. The calcium channels abandoned the clusters when they grabbed onto the decoys rather than real potassium channels.
The process known as excitation-transcription coupling, which links changes in neuronal electrical activity to changes in gene expression, is vital for brain functions like learning and memory.
“The idea is to take advantage of this knowledge, to use it as an opportunity to look at how neurons actually work,” Trimmer said. “We all learn the fundamentals of neuroscience in college, but there are many interesting things that we still don’t understand.”
“There are a variety of calcium channels, but the sort that can be found in these clusters is required for converting changes in electrical activity to changes in gene expression,” Trimmer added. “We discovered that if you disrupt the calcium-signaling proteins present at these odd clusters, you break the excitation-transcription link, and the neurons lose function.”
“We’re excited about this,” Trimmer told me. “It’s like our vision was correct, and now we’re seeing the proof. We’re hoping that our discovery will lead to new avenues of research.”
“Many studies have been done on calcium signaling in dendrites – the sites where neurons receive information from other neurons. However, there was no known function for these much larger structures on the cell body in neuron physiology.” — Nicholas C. Vierra
“We are at the start of our understanding of this signaling’s significance, but these new findings might provide information that may be useful in future studies looking into its role in brain function and possibly even the creation of new types of medicines,” Trimmer added.
This finding reveals a new molecular mechanism in the brain that regulates how neurons may transmit electrical signals to one another.
“This is not yet a treatment or cure, but it certainly gives us a lot of information about how neurons work that we didn’t understand before,” Vierra said. “And it’s exciting because now we have a new target to think about with respect to how neuronal signaling is affected by calcium.”
This finding may be useful in future studies looking into its role in brain function and possibly even the creation of new types of medicines.