{"id":51531,"date":"2025-11-27T14:09:49","date_gmt":"2025-11-27T13:09:49","guid":{"rendered":"https:\/\/fgu.cas.cz\/?p=51531"},"modified":"2025-11-27T14:22:40","modified_gmt":"2025-11-27T13:22:40","slug":"a-new-cholesterol-binding-site-a-new-target-for-cognitive-deficit-and-pain-treatment","status":"publish","type":"post","link":"https:\/\/fgu.cas.cz\/en\/2025\/11\/a-new-cholesterol-binding-site-a-new-target-for-cognitive-deficit-and-pain-treatment\/","title":{"rendered":"A New Cholesterol Binding Site: A New Target for Cognitive Deficit and Pain Treatment"},"content":{"rendered":"

The Hidden Power of Two Key Brain Receptors<\/strong><\/p>\n

Muscarinic and opioid receptors are among the most important proteins in the brain that transmit chemical signals into cells. Muscarinic receptors regulate memory, attention, mood, and various everyday functions, including digestion and heart rate. When they malfunction, diseases such as Alzheimer\u2019s disease, depression, or schizophrenia may develop. Opioid receptors are equally important\u2014they control pain perception, mood, and sleep, making them crucial targets for treating chronic pain and mood disorders. However, current drugs that activate these receptors often cause unpleasant side effects such as excessive sweating, constipation, or respiratory depression, which limit their clinical use.<\/p>\n

A Surprising Discovery: A Shared Cholesterol-Binding Site<\/strong><\/p>\n

Scientists from the Laboratory of Neurochemistry<\/a> at IPHYS have made a remarkable discovery: both muscarinic and opioid receptors share an unexpected feature\u2014a cholesterol-binding site that functions in a completely new way. Using advanced molecular dynamics simulations, the team identified a non-canonical cholesterol-binding site located at a critical point in receptor architecture\u2014specifically on the sixth transmembrane helix, involving a key amino acid known as arginine 6.35.<\/p>\n

Unlike previously known cholesterol-binding patterns, this newly identified site works through a fundamentally different mechanism. It does not follow the well-known \u201cCRAC\u201d or \u201cCCM\u201d binding motifs that scientists have studied for years. Instead, cholesterol fits into a narrow groove between the sixth and seventh transmembrane helices, where it directly interacts with the receptor through hydrophobic interactions and hydrogen bonding.<\/p>\n

How This Changes Drug Development<\/strong><\/p>\n

This discovery opens entirely new avenue for developing \u201csmarter\u201d medications. The research showed that when cholesterol binds to this site, it differentially modulates these two receptor types: it dampens the activity of muscarinic receptors while enhancing the activity of opioid receptors. In other words, cholesterol acts as a natural \u201cbrake\u201d on muscarinic receptors but as an \u201caccelerator\u201d for opioid receptors.<\/p>\n

 <\/p>\n

The greatest promise lies in tissue-specific drug targeting. Since different tissues contain varying amounts of cholesterol, drugs designed to target this cholesterol-binding site could theoretically be more selective\u2014working effectively in some tissues while \u201cavoiding\u201d others. For instance, neural tissues (the brain and spinal cord) are particularly rich in cholesterol, whereas smooth muscle cells contain much less cholesterol. By designing sterol-based therapeutic molecules, scientists could create medications that preferentially affect the brain while sparing peripheral tissues, potentially minimising the unwanted side effects that plague current treatments.<\/p>\n

This approach reflects a growing interest in positive allosteric modulators (PAMs)\u2014drugs that enhance natural signalling without directly activating receptors\u2014 offering a path toward safer, more selective pain management and cognitive disorder treatments.<\/p>\n

Reference:<\/strong> Chetverikov N., Janou\u0161kov\u00e1 – Rand\u00e1kov\u00e1 A., Nelic D., Jakub\u00edk J.: Cholesterol differentially modulates the activity of opioid and muscarinic receptors via a common binding site. Biochemical Pharmacology<\/em> 242:117296 (2025). IF = 5.6. DOI: 10.1016\/j.bcp.2025.117296<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

The Hidden Power of Two Key Brain Receptors Muscarinic and opioid receptors are among the most important proteins in the brain that transmit chemical signals into cells. Muscarinic receptors regulate memory, attention, mood, and various everyday functions, including digestion and heart rate. When they malfunction, diseases such as Alzheimer\u2019s disease, depression, or schizophrenia may develop. […]<\/p>\n","protected":false},"author":11,"featured_media":51542,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"categories":[113],"tags":[],"class_list":["post-51531","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-important-success"],"acf":[],"_links":{"self":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/posts\/51531","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/users\/11"}],"replies":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/comments?post=51531"}],"version-history":[{"count":0,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/posts\/51531\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/media\/51542"}],"wp:attachment":[{"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/media?parent=51531"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/categories?post=51531"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/fgu.cas.cz\/en\/wp-json\/wp\/v2\/tags?post=51531"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}