Researchers discover structure, role, of cannabinoid receptor
The endocannabinoid system (ECS) has become a focus in integrative medicine for its role in endocrine function, energy balance, and secretion of hormones related to stress responses. Researchers have been trying to better understand the complex SYSTEM and its cannabidiol receptors and proteins, which are expressed throughout the nervous system, including the brain.
Now, a new study aims to obtain the crystal structure of the human type 2 cannabinoid receptor, with the hope that findings will help develop treatment protocols against inflammatory, neurodegenerative, and other chronic diseases, according to the paper recently published in the journal Cell.
Two cannabinoid receptors, CB1 and CB2, comprise the ECS, which regulates biological processes such as metabolism, pain sensation, neuronal activity, and immune function, according to researchers from the Moscow Institute of Physics and Technology in Russia, who collaborated with researchers from the University of Southern California in Los Angeles. Cannabinoid receptors can be targeted to alleviate certain pathological conditions, including chronic pain, experts say.
While the CB1 receptors are mostly found in the nervous system and are responsible for psychoactive effects, the CB2 receptors are predominantly present in the immune system. Studies indicate that CB2 is a promising target for immunotherapy, as well as treating inflammatory and neuropathic pain, and neurodegenerative diseases. It has also been shown that molecules blocking CB2 can reduce tumor growth, according to researchers.
To effectively treat pathological conditions, drugs need to specifically target CB1 or CB2. However, the two receptors are very much alike. The amino acid sequences that encode them are 44 percent identical. Developing a selective medicine requires knowing the structure of both targets in detail, researchers say. Unlike CB1, the structure of CB2 has remained unknown until now.
To identify the shape of an individual molecule, researchers make a crystal from many such molecules. When arranged in this highly ordered way, the molecules can be exposed to x-rays, revealing their structure. The research team made a crystal from CB2 receptors bound to molecules blocking this receptor, which are potential drug candidates. The x-ray analysis allowed the team to see both the structure of CB2 and how it connects to the blocking molecule, or antagonist.
Receptors are unstable proteins by nature, researchers say. To study them, they need to be modified using genetic engineering. This involves introducing mutations that make the protein stable without changing its structure or function. Thus, the research team used software to predict mutations potentially useful for stabilizing receptor molecules, and then tested them experimentally, according to the study.
The researchers contrasted the structure of CB2 with that of CB1. They concluded that substances activating one of the receptors can weaken or inhibit the other, and vice versa. This opens a possibility not just for drugs that target exclusively one receptor, researchers say, but those that affect both receptors in different ways.