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Cannabinoid receptor 1 (CB1) mediates the functional responses of Δ-tetrahydrocannabinol (Δ-THC). Although progress has been made in understanding cannabinoid binding and receptor activation, detailed knowledge of the dynamics involved in the activation mechanism of CB1 is lacking. Here, we use recently determined CB1 crystal structures to analyze its transition from inactive to active state by performing unbiased microsecond-length molecular dynamics (MD) simulations, totaling 32 μs, with and without bound potent cannabinoid agonist CP-55940. CB1 activation is characterized by an upward axial movement of transmembrane (TM) helix 3, inward movement of TM7 and outward movement of TM6. These conformational changes collectively allow Gi protein docking, although fully active states of the receptor occur only transiently during MD simulations. Additionally, positive allosteric modulation of CB1 by anionic phospholipids is found to increase action of the bound agonist. Specifically, this involves protein-lipid interactions at intracellular loop 3, TM6, and ionic-lock residue Arg214.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Cannabinoid receptor (CBR) agonist could act as a protective agent against seizure susceptibility in animal models of epilepsy. Studies have shown that potassium channels could play a key role in amel...
Patients under cannabis-based therapies are usually chronically exposed to cannabinoids. Chronic treatment with a cannabinoid receptor agonist, WIN 55,212-2, affects brain metabolism and modifies func...
The cannabinoid type 2 receptor (CB) has recently emerged as an important therapeutic target for cancer as well as cardiovascular diseases. The CB receptor downregulation has been reported in solid tu...
Evidence suggests that cannabinoid-1 receptor (CB1R) activation is associated with increased food intake and body weight gain. Human epidemiological studies, however, show decreased prevalence of obes...
The administration of cannabinoid receptor 2 (CB2R) agonist has been reported to produce a cardioprotective effect against the pathogenesis and progression of myocardial infarction (MI). Here in this ...
The aims this study is to explore the effect of a GLP-1 receptor agonist on the degree of brain activation and connectivity obtained by functional magnetic resonance imaging in lean and ob...
The aim of this research project is to design a new model of human itch by application of Zyclara cream. Further, the aim is to characterize the model and to verify if the mechanism of act...
This is an open-label extension study for participants of the randomized placebo-controlled, double-blind, parallel-group, enriched enrolment randomized withdrawal NMS-Nab Study, assessing...
This study evaluates the treatment of the symptoms of deep endometriosis with a cannabinoid derivate.
The goal of this study is to determine if supplementation with krill oil concentrate containing the phospholipid-bound omega-3 fatty acids improves performance on specific cognitive tests ...
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activa
A subclass of cannabinoid receptor found primarily on immune cells where it may play a role modulating release of CYTOKINES.
A subclass of cannabinoid receptor found primarily on central and peripheral NEURONS where it may play a role modulating NEUROTRANSMITTER release.
Compounds that interact with and stimulate the activity of CANNABINOID RECEPTORS.
Compounds that inhibit or block the activity of CANNABINOID RECEPTORS.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...