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Allosteric Modulation of CB 1 by Pregnenolone
Author(s) -
Spaeth Justin,
Camacho Alex,
Rios Brigitte,
McKinney Tariq,
Miller Aaron
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb60
Subject(s) - allosteric regulation , allosteric modulator , pregnenolone , pregnenolone sulfate , neuroactive steroid , chemistry , pharmacology , neuroscience , cannabinoid receptor type 2 , receptor , cannabinoid receptor , gabaa receptor , biochemistry , biology , agonist , steroid , hormone
The endocannabinoid system plays a role in diverse conditions such as anxiety, addiction, eating and memory disorders. Endocannabinoids are produced by postsynaptic neurons and activate receptors on presynaptic neurons in order to decrease neurotransmitter release. In the brain, the most important receptor activated by endocannabinoids is cannabinoid receptor type 1 (CB 1 ). Tetrahydrocannabinol (THC), the active ingredient in marijuana, also activates this receptor. THC and similar drugs have therapeutic potential in the treatment of pain, Alzheimer's disease, anxiety, arthritis, and cancer. A downside to the medicinal use of THC is that it also induces psychotropic effects. Recently, it was discovered that pregnenolone binds to CB 1 , where it acts as an allosteric modulator that decreases the effects of THC. An allosteric modulator is a molecule that modifies receptor function by binding somewhere other than the active site. Discovery of allosteric modulators is significant because it means that there may be additional ways to target CB 1 that have a reduced rate of psychotropic effects. The Messmer SMART (Students Modeling a Research Topic) Team has created a model of CB 1 bound to pregnenolone using 3D printing technology. Our model highlights the amino acids E133 and R409, which form hydrogen bonds with pregnenolone and are required for its binding to the allosteric site of CB 1 . Studying the interaction between CB 1 and pregnenolone will allow for a greater understanding of the interaction between synaptic function and pregnenolone levels as well as the design of additional allosteric modulators for testing as therapeutics. This program is supported by a grant from NIH‐CTSA.