“A New Way Biology Works”: Neuronal signals can be modified by mirror-image molecules

Summary: Researchers discovered that the orientation of a single amino acid in a sea snail can determine which neuron receptor is activated, resulting in different types of neuronal activity. This finding sheds light on how the brain can regulate communication between cells in different ways.

Source: University of Nebraska Lincoln

Using some sea snails, chemists at the University of Nebraska-Lincoln have discovered that one of the smallest imaginable changes to a biomolecule can produce one of the largest imaginable consequences: controlling the activation of neurons.

Their discovery came from studying peptides, the short chains of amino acids that can transmit signals between cells, including neurons, while populating the central nervous system and bloodstreams of most animals.

Like many other molecules, an amino acid in a peptide can take one of two forms that have the same atoms with the same connectivity but in a mirror-image orientation: L and D.

Chemists often think of these two orientations as the left and right hands of a molecule. The L orientation is by far the most common in peptides and is even considered the standard. But when enzymes turn an L into a D, the seemingly minor reversal can, for example, turn a potentially therapeutic molecule into a toxic molecule, or vice versa.

Now, Husker chemists James Checco, Baba Yussif, and Cole Blasing have discovered a whole new role for this molecular mirroring. For the first time, the team has shown that the orientation of a single amino acid – in this case one of dozens found in a sea snail’s neuropeptide – can determine the likelihood that the peptide will activate one neuron receptor over another.

Because different types of receptors are responsible for different neuronal activities, the finding suggests another means by which a brain or nervous system can regulate the labyrinthine, life-sustaining communication between its cells.

“We discovered a new way that biology works,” said Checco, an assistant professor of chemistry in Nebraska. “In this way, nature helps the peptide go to one signaling pathway and not the other. And understanding more about this biology will help us to use it for future applications.”

Checco’s interest in neuropeptide signaling dates back to his postdoctoral days when he came across the first study showing evidence for a peptide with a D-amino acid activating a neuron receptor in sea snails. This particular receptor only responded to the peptide when it contained the D-amino acid, making its switching from L to D much like an on/off switch.

Eventually, Checco would identify a second such receptor himself. Contrary to the one that originally piqued his interest, Checco’s receptor responded to both a peptide containing all of the L-amino acids and the same peptide containing a single D.

But the receptor also responded more strongly to the All-L peptide and activated when introduced at lower concentrations than its D-containing counterpart. Instead of an on/off switch, Checco seemed to have found something closer to a dimmer.

“We were like, ‘Is that the whole story?'” Checco said. “What’s really going on? Why make this D molecule when it activates the receptor even worse?”

The team’s latest findings, detailed in the journal Proceedings of the National Academy of Sciences, Indicating an answer inspired by a hypothesis. Perhaps, the team thought, there are other receptors in the sea snail that are sensitive to this D-containing peptide. If so, maybe some of those receptors would respond differently.

Yussif, a PhD student in chemistry, set to work looking for sea slug receptors whose genetic blueprints resembled those discovered by Checco. He eventually narrowed down a list of candidates that the team could then clone and express in cells before introducing them with the same D-containing peptide as before.

One of the receptors responded. But this receptor – in an almost mirror-image performance of Checco’s original – responded much more favorably to the D-containing peptide than its all-L counterpart.

“You can see a pretty dramatic shift,” Checco said, “where now the D is actually much more effective than the L at activating this new receptor.”

In fact, the team realized that targeting this lone amino acid guided their peptide to activate either one receptor or the other. In its All-L state, the neurotransmitter preferred Checco’s original. When the certain L became a D, however, it went for Yussif’s new candidate.

Central nervous systems rely on different types of neurotransmitters to send different signals to different receptors, with dopamine and serotonin being among the most well known in humans. However, given the radical complexity and subtlety of signaling in many animals, it makes sense that they could develop similarly sophisticated methods of fine-tuning the signals sent by even a single neuropeptide, Checco says.

“These kinds of communication processes need to be very, very heavily regulated,” Checco said. “You have to make the right molecule. It has to be released at the right time. It has to be published in the right place. It actually needs to be mined in a certain amount of time so you don’t have too much signaling.

“So you have all these regulations,” he said, “and now this is a whole new level of it.”

“We discovered a new way that biology works,” said Checco, an assistant professor of chemistry in Nebraska. The image is in the public domain

Unfortunately for Checco and others like him, naturally occurring peptides containing D-amino acids are difficult to identify with the instruments readily available to most laboratories. He suspects that this is one reason why no D-containing peptides have been found in humans, at least so far. He also suspects that’s about to change — and if it does, it could help researchers better understand both the function and disease-related dysfunction of signaling in the brain.

“I think it’s likely that we’ll find peptides with this type of modification in humans,” Checco said. “And that will potentially open up new therapeutic avenues related to this specific target.” It could be exciting there to learn more about how these things work.”

Meanwhile, Checco, Yussif, and Blasing, a senior double major in biochemistry and chemistry, try to answer other questions. For starters, they wonder if a peptide containing only L or D—even those equally likely to activate a receptor—might activate that receptor in different ways, with different cellular consequences. And the search for receptors doesn’t stop either.

“This is one receptor system, but there are others,” Checco said. “I think we want to start expanding and discovering new receptors for more of these peptides to really get a fuller picture of how this modification affects signaling and function.

“What I really want to go with this project long-term,” he said, “is to get a better idea across biology of what this modification does.”

Summary created with ChatGPT AI technology

About this news from neuroscientific research

Author: Scott Schrage
Source: University of Nebraska Lincoln
Contact: Scott Schrage – University of Nebraska Lincoln
Picture: The image is in the public domain

Original research: Closed access.
“Endogenous isomerization of l- to d-amino acid residues modulates selectivity between different members of the neuropeptide receptor family” by James Checco et al. PNAS


Endogenous isomerization of l- to d-amino acid residues modulates selectivity between different members of the neuropeptide receptor family

The isomerization of L- to D-amino acid residues of neuropeptides is a little-studied post-translational modification found in animals in several phyla. Despite its physiological importance, little information is available on the effects of endogenous peptide isomerization on receptor recognition and activation. As a result, the full roles played by peptide isomerization in biology are not well understood.

Here we see that the aplysia The allatotropin-related peptide (ATRP) signaling system utilizes l- to d-residue isomerization of an amino acid residue in the neuropeptide ligand to modulate selectivity between two distinct G protein-coupled receptors (GPCRs).

We first identified a novel receptor for ATRP that is selective for the D2 form of ATRP bearing a single d-phenylalanine residue at position 2. Using cell-based receptor activation experiments, we then characterized the stereoselectivity of the two known ATRP receptors for both endogenous ATRP diastereomers and homologous toxin peptides from a carnivorous predator.

We found that the ATRP system showed dual signaling through both the GαQ and GaS pathways, and each receptor was selectively activated by one naturally occurring ligand diastereomer over the other. Taken together, our results provide insights into an unexplored mechanism by which nature regulates intercellular communication.

Given the challenges in de novo detecting l- to d-residue isomerization from complex mixtures and in identifying receptors for novel neuropeptides, it is likely that other neuropeptide-receptor systems can also take advantage of changes in stereochemistry to enhance receptor selectivity modulate in a similar way discovered here.

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