What if our changing moods, with their ups and downs, depend in part on a brain fat molecule that could be manipulated to improve our mental health? This is the whole point of the important discovery made by an American team of pharmacologists and just published in the journal Science Advances. This recent work could indeed accelerate the development of new-generation antidepressants and antipsychotics, more quickly effective than those currently available, which often take two to three weeks to work.
Pharmacology researchers at the Icahn School of Medicine at Mount Sinai have focused very closely on a major brain receptor among the hundreds known to date, 5-HT1A, the most widespread of the receptors for serotonin, this neurotransmitter well known for example in depression and against which drugs like Selective serotonin reuptake inhibitors (SSRIs) have been developed and are now very frequently used in psychiatry.
Expressed particularly in the brain but also in the spleen, 5-HT1A located in the presynaptic and postsynaptic regions remains poorly understood to date. Despite its major clinical importance, few precise studies have been conducted on the mechanisms regulating it.
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A phospholipid as co-pilot
Using innovative laboratory techniques such as high-resolution cryo-electron microscopy—a cutting-edge imaging technology that reveals molecular structures at near-atomic resolution—the team led by David Wacker, assistant professor of pharmacological sciences and neuroscience at the Icahn School of Medicine at Mount Sinai, has for the first time uncovered the key role of a lipid molecule, a phospholipid found in cell membranes, in controlling 5-HT1A activity. It could be called a hidden co-pilot.
An important discovery allowing us to better understand this receptor which “ is like a control panel that helps manage brain cells' response to serotonin, a key chemical involved in mood, emotions, and cognition, explains lead author Daniel Wacker in a press release. NOTbone The results shed light on how it works, what switches it activates, how it fine-tunes signals, and where its limits lie.
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Certain cell signaling pathways favored
Pharmacologists have also demonstrated that the 5-HT1A receptor is intrinsically programmed to favor certain cell signaling pathways over others, regardless of the drug used to target it. But drugs can nevertheless influence the intensity of activation of these pathways. The researchers were able to map receptor activation along these different pathways.
For Audrey Warren, lead author of this work, a former student of the Wackerlab and now a researcher at Columbia University, " Our work provides a molecular map of how different drugs act on this receptor, activating or inhibiting specific pathways that influence brain function.” There is no doubt in any case that an important step in the understanding of the cerebral receptor has just been taken, notably with this unprecedented discovery of the role of a phospholipid whose involvement will still have to be clarified thanks to new studies.
This work will then need to be put into practice with the development of " new, faster, and more effective drugs not only for depression, but also for conditions like psychosis and chronic pain. This is a key piece of the puzzle." concludes David Wacker.
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