When the word “marijuana” is mentioned, the first thing that many people think of is “addictive plants” and “traditional drugs”. But in fact, hemp is an ancient crop that was originally used to make ropes and clothes, and can even be counted as one of the “grains”. “The Rites of Zhou·Tianguan·Yi Yi” mentioned that “the five flavors, five grains, and five medicines are used to nourish the disease.” Among them, the “five grains” include hemp, millet, millet, wheat, and beans.
As for its psychoactive effects, the ancient Greek historian Herodotus’ “History” written in the 5th century BC has a description of “the Scythians on the Eurasian steppes burning hemp seeds.” It is generally believed that humans The earliest written evidence of marijuana use. In the “Shen Nong’s Materia Medica”, the earliest extant traditional Chinese medicine book in China, there is also a record that “eating too much Ma Bi can cause people to see ghosts, walk wildly, and taking it for a long time can lead to spiritual enlightenment.”
It is undeniable that cannabis is a “love-hate” existence – in addition to addiction, cannabis also has important medicinal values.
The main reason why marijuana is addictive and harmful is cannabinoid, which consists of two components: psychoactive tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD). The latter, CBD, is an important source of cannabis’ medicinal value.
As the medical community continues to conduct in-depth investigations, more and more studies have discovered the efficacy of CBD, including treating stress, anxiety, insomnia, chronic pain, inflammation and other diseases. At the same time, a large number of clinical trials have shown that CBD is an effective drug for treating some forms of epilepsy and pain; as early as 2018, the FDA approved CBD for the treatment of two severe and rare forms of epilepsy.
A large number of studies have confirmed the interaction between CBD and various proteins, especially membrane proteins. But which target and pathway is the most important target for CBD to treat epilepsy or pain?
According to previous research, one of the functions of CBD is to inhibit voltage-gated sodium (Nav) channels. Similar to many drugs that inhibit Nav channels, CBD’s interaction with Nav channels is state-dependent—CBD binds with higher affinity to the closed resting state of Nav channels than to the channel’s closed, inactive state.
Cryo-electron microscopy structure of human Nav1.7-CBD complex (picture from Nature Communications)
However, at physiological membrane potential, Nav channels are in a highly voltage-dependent equilibrium state between resting and inactivation. Therefore, even if the drug binds to closed-state channels, the tight binding of CBD to inactive channels will lead to a reduction of activated resting-state channels under the action of the coupling balance mechanism.
In order to obtain a more specific mechanism, Yan Ning from Princeton University/Tsinghua University and Bruce P. Bean of Harvard Medical School jointly published a research paper titled Cannabidiol inhibits Nav channels through two distinct binding sites online in Nature Communications, revealing that CBD Interacts with Nav1.7 channels in a state-dependent manner at submicromolar concentrations.
doi: 10.1038/s41467-023-39307-6
Electrophysiological experiments show that CBD binds more closely to the inactivated state than the resting state; specifically, CBD can bind to the inactivated Nav1.7 channel with a dissociation constant of approximately 50nM.
Further, the researchers obtained the cryo-electron microscopy structure of CBD binding to the human Nav1.7 channel and discovered two different binding sites.
One binding site is located near the inactivating “wedge” of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, known as the I-site of CDB-1. Can mediate a stable rapid inactivation state. By increasing binding to the IFM motif, it results in a voltage-dependent equilibrium shift between resting and inactive channels and a slowing of recovery from the inactive state when the membrane is repolarized.
The other binding site, the F-site of CDB-2, is located in the IV-I fenestration near the upper pore; CBD binds to it in a conservative manner.
Conformational changes of Nav1.7 when CBD binds to the I-site
The researchers concluded that the results of this study were unexpected! CBD binds to two distinct sites on the Nav1.7 channel, but these two sites are distinct from the binding sites of other small molecule state-dependent Nav inhibitors previously identified in structural data of mammalian Nav1 channels.
The research carried out by Yan Ning’s team has important practical significance – after accurately identifying the binding site between CBD and the Nav1.7 channel, specific drugs targeting the Nav channel can be developed based on this structure, which will help Avoid some of the side effects of CBD in the treatment of epilepsy, thereby benefiting more patients.
