First atomic-level image of the human 'marijuana receptor' unveiled
October 20, 2016
Science Daily/Scripps Research Institute
In a discovery that advances the understanding of how marijuana works in the human body, an international group of scientists, including those from the Florida campus of The Scripps Research Institute (TSRI), have for the first time created a three-dimensional atomic-level image of the molecular structure activated by tetrahydrocannabinol (THC), the active chemical in marijuana.
The new insights into the human cannabinoid receptor 1 (CB1) will provide an essential tool for understanding why some molecules related to THC have unexpectedly complex and sometimes harmful effects. The findings also have the potential to guide drug design for pain, inflammation, obesity, fibrosis and other indications.
The new study, published by the journal Cell, was led by a quartet of scientists: TSRI's Laura Bohn, Northeastern University's Alexandros Makriyannis, Shanghai Tech University's Zhi-Jie Liu and Raymond C. Stevens (also of the University of Southern California).
At the beginning of the study, the team struggled to produce a crystal form -- needed to obtain data to recreate the high-resolution structure -- of the receptor bound with AM6538, a stabilizing a molecule that blocks the receptor's action.
"The CB1 receptor proved as challenging for crystallization as it did for understanding its functional regulation and signaling," said Bohn, who is a professor in TSRI's Department of Molecular Therapeutics.
When the scientists succeeded in crystalizing the receptor and collecting the data, the structure of the cannabinoid receptor complex revealed an expansive and complicated binding pocket network consisting of multiple sub-pockets and channels to various regions of the receptor.
Cannabinoid receptors are part of a large class of receptors known as G protein-coupled receptors (GPCR), which account for about 40 percent of all prescription pharmaceuticals on the market, and play key roles in many physiological functions. When an outside substance binds to a GPCR, it activates a G protein inside the cell to release components and create a specific cellular response.
AM6538, is an antagonist/inverse agonist that binds tightly to the receptor; it has a long half-life, making it potentially useful as a treatment of addiction disorders.
"As marijuana continues to become more common in society, it is critical that we understand how it works in the human body," said Liu, who is professor and deputy director of the iHuman Institute of Shanghai Tech and is also affiliated with the Chinese Academy of Sciences.
https://www.sciencedaily.com/releases/2016/10/161020223928.htm
Mulling the marijuana munchies: How the brain flips the hunger switch
February 18, 2015
Science Daily/Yale University
The "munchies," or that uncontrollable urge to eat after using marijuana, appear to be driven by neurons in the brain that are normally involved in suppressing appetite, according to a new study by Yale School of Medicine researchers in the Feb. 18 issue of the journal Nature.
Lead author Tamas Horvath and his colleagues set out to monitor the brain circuitry that promotes eating by selectively manipulating the cellular pathway that mediates marijuana's action on the brain, using transgenic mice.
"By observing how the appetite center of the brain responds to marijuana, we were able to see what drives the hunger brought about by cannabis and how that same mechanism that normally turns off feeding becomes a driver of eating," said Horvath, the Jean and David W. Wallace Professor of Neurobiology and of Obstetrics, Gynecology, and Reproductive Sciences, director of the Yale Program in Cell Signaling and Neurobiology of Metabolism, and chair of the Section of Comparative Medicine.
"It's like pressing a car's brakes and accelerating instead," he said. "We were surprised to find that the neurons we thought were responsible for shutting down eating, were suddenly being activated and promoting hunger, even when you are full. It fools the brain's central feeding system."
In addition to helping explain why you become extremely hungry when you shouldn't be, Horvath said, the new findings could provide other benefits, like helping cancer patients who often lose their appetite during treatment.
Researchers have long known that using cannabis is associated with increased appetite even when you are full. It is also well known that activating the cannabinoid receptor 1 (CB1R) can contribute to overeating. A group of nerve cells called pro-opiomelanocortin (POMC) neurons are considered as key drivers of reducing eating when full.
"This event is key to cannabinoid-receptor-driven eating," said Horvath, who points out that the feeding behavior driven by these neurons is just one mode of action that involves CB1R signaling. "More research is needed to validate the findings." Whether this primitive mechanism is also key to getting "high" on cannabis is another question the Horvath lab is aiming to address.
https://www.sciencedaily.com/releases/2015/02/150218072757.htm
Marijuana-like Compounds Suppress the Immune Response
April 26, 2006
Science Daily/American Society for Biochemistry and Molecular Biology
A group of Japanese scientists has discovered that cannabinoids can cause some white blood cells to lose their ability to migrate to the sites of infection and inflammation. These findings, which appear in the May 5 issue of the Journal of Biological Chemistry, could have potential use in the development of novel anti-inflammatory drugs.
The cannabinoids are a group of chemicals that include marijuana. These compounds bind to and activate the body's cannabinoid receptors. There are two types of cannabinoid receptor: the peripheral cannabinoid receptor (CB2) which is predominantly found in immune cells, and the central cannabinoid receptor (CB1) which occurs in the central nervous system.
Recent studies have suggested that CB2 may be involved in a wide range of physiologic phenomena related to immunity, although research on this function is still at an early stage. Among the possible immunological roles for CB2 is an involvement in the initiation of white blood cell migration to sites of infection and inflammation.
In the Journal of Biological Chemistry study, which was featured as a "Paper of the Week", Yumi Tohyama and colleagues used an in vitro model of blood cell migration to study the involvement of CB2 in the recruitment white blood cells. They found that treating the blood cells with compounds that bind to CB2 suppresses the migration of the cells. When they examined the cells, they discovered that they had lost their ability to develop a front/rear polarity, which is something they need to effectively migrate to sites of infection and inflammation.
Because cannabinoids seem to suppress activated white blood cells, Tohyama believes they could have a potential use in the treatment of inflammatory diseases.
The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at www.jbc.org.
The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, the Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings.
https://www.sciencedaily.com/releases/2006/04/060426174508.htm