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Revealing the mechanism of agonist-mediated cannabinoid receptor 1 (CB1) activation and phospholipid-mediated allosteric modulation.

08:00 EDT 16th May 2019 | BioPortfolio

Summary of "Revealing the mechanism of agonist-mediated cannabinoid receptor 1 (CB1) activation and phospholipid-mediated allosteric modulation."

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.

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This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
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Medical and Biotech [MESH] Definitions

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

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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.

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