How Nerve Cells Get Ready To Fire: Utah Biologists Demonstrate A Protein's Key Role In Nerve Signals

Nematode worms were paralyzed - unable to move, eat or eliminate waste - when the scientists crippled the protein, which is named UNC-13 for "uncoordinated" and is found in all animals examined so far.

"All our thoughts and memories are coded by connections in the brain, and these tend to be chemical connections," said Erik M. Jorgensen, an associate professor of biology at the U of U. "This protein may be one of the key proteins in strengthening the connections among nerve cells in your brain so that memories are stored." Future research will aim to determine if that is true, he said.

In a new study, Jorgensen and colleagues demonstrated that UNC-13 is necessary for helping another protein - named syntaxin - collect balloon- or bubble-like packets of neurotransmitters inside a nerve cell, then release the chemicals so they send a signal to an adjacent neuron.

Jorgensen, research assistant professor Janet E. Richmond and doctoral student Robby M. Weimer published their findings in the July 19 issue of the journal Nature.

Researchers elsewhere previously discovered the UNC-13 gene and protein. The new study revealed molecular details of how the UNC-13 protein primes or "cocks" the trigger - syntaxin - that is most responsible for propelling neurotransmitters out of one neuron and toward the next nerve cell.

Syntaxin is shaped somewhat like a catapult. If the protein is folded or "closed," membrane bubbles filled with neurotransmitters cannot stick to syntaxin. But if the syntaxin protein is "open" - like a catapult ready to fire - the chemical-filled bubbles stick to it. Then the bubbles fuse to the inside wall of the nerve cell. When that happens, the neurotransmitter chemicals are released from the bubbles and the entire nerve cell, sending the chemical nerve signal to the next neuron.

In a series of experiments, Jorgensen showed that without the UNC-13 protein, the syntaxin protein remains closed and cannot help a nerve cell release neurotransmitters. Thus, the UNC-13 protein unfolds or opens the syntaxin protein so it can aid the release of neurotransmitter chemicals from one nerve cell to the next.

"We demonstrated what UNC-13 does," Jorgensen said. "It grabs syntaxin and opens it up like a catapult. It cocks it like catapult."

When a human or other animal has any sensation - from feeling pain to hearing a sound to remembering something - millions of neurons are sending signals to each other in the form of neurotransmitter chemicals, Jorgensen said. The strength of the signal depends on the number of neurotransmitter-filled membrane balloons that are released by each neuron. So the strength of a memory depends on how well the UNC-13 protein helps gather up neurotransmitter-filled balloons and release them from one nerve cell to the next, he added.

"A memory is the strength of the connection between a speaking cell and a listening cell," Jorgensen said. "The memory of your grandmother doesn't exist as single cell somewhere in your brain. That memory instead is held in your brain as a million different connections among nerve cells. "When you see your grandmother, there are signals that come from the visual system that say 'old' and 'woman,' and another signal that says 'family member.' All these things converge for you to recognize your grandmother. When all of those converge upon some group of cells, that is the signal for you to recognize your grandmother."

Earlier studies have shown that the strength of memory is greater if the nerve cell receiving or "listening to" a signal has more receptors for neurotransmitters. He said the new study suggests the strength of a memory also depends on the amount of neurotransmitter sent by a nerve cell that is sending a signal or "talking."

Jorgensen said the research was aimed at "understanding how the brain works, how information is stored and transmitted. The connection between nerves cells stores information and transmits it. What this study has shown is what molecules control the strength of those connections and thus how information is stored and transmitted."

Nematode worms were used for the study because they reproduce quickly, it is simple to generate mutations in them to study proteins involved in nerve signals, and they use the same nervous system chemicals as humans and other animals. Nematodes are common in soil but are tiny, measuring only about 1 millimeter long.