An Analysis of the Putative CBD Binding Site in the Ionotropic Cannabinoid Receptors.

Spread the love

. 2020 Dec 9;14:615811.

doi: 10.3389/fncel.2020.615811. eCollection 2020.


Item in Clipboard

Chanté Muller et al. Front Cell Neurosci. .


Cannabinoids have been long studied for their therapeutic properties, particularly for their use in the treatment of pain. As new therapies are sought after to treat conditions of chronic pain, so is a better understanding of the ligands and their target receptors or channels. A recently published cryo-EM structure showed the putative binding location of a well-known cannabinoid ligand, cannabidiol (CBD), in TRPV2, a channel that has been implicated in inflammation and chronic pain. TRPV2, along with TRPV1, TRPV3, TRPV4, TRPA1, and TRPM8 all have the capability to be modulated by cannabinoid ligands and are located in the peripheral nervous system. Here, we analyze the putative CBD binding site in each of these channels and compare structural and sequential information with experimental data.

Keywords: TRP channels; TRPA1; TRPM8; TRPV1; TRPV2; TRPV3; TRPV4; cannabidiol.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Figure 1

Figure 1

A truncated version of the human sequence alignment of six ionotropic cannabinoid receptors and rTRPV2. CBD has been resolved in rTRPV2 in two separate states and residues within 10 Å of the putative binding site of CBD have been highlighted and are shown here as a reference (yellow row). Comparable regions within the human ionotropic cannabinoid receptors have been aligned. Residues within hTRPV1 (red row), hTRPV2 (orange row), hTRPV3 (green row), hTRPV4 (blue row), hTRPA1 (purple row), and hTRPM8 (pink row) that are the same as the reference (rTRPV2) are shown in pale green. Residues that are of a similar type to the reference are shown in orange, and divergent residues are shown in red. The double starred residues, L537 and Y634, indicate the two residues that were noted to have rotameric changes from the apo to the CBD-bound structure of rTRPV2 and are visualized in Figure 2. Single starred residues are within 5 Å of bound CBD and are marked for easy vertical comparison across the ionotropic cannabinoid receptors.

Figure 2

Figure 2

(A) A close up of CBD (pink) bound in rTRPV2 (adapted from PDB: 6U88) with Y634 and L537 in cyan. Helices S1–S4 and S6 are shown as cartoon tubes with S5, the pore helix, and the TRP domain shown as cartoon ribbons. (B) A close up of hTRPV3 (adapted from PDB: 6MHO) with comparable residues F666 and V587 shown in cyan. Helices S1–S4 are shown as cartoon tubes and S5-TRP domain are shown as cartoon ribbons. (C) A close up of Xenopus tropicalis TRPV4 (adapted from PDB: 6BBJ) which shares 78% sequence homology with human TRPV4. F703 and L610 are shown in cyan. Helices S1–S4 are shown as cartoon tubes, and S5-TRP domain are shown as cartoon ribbons.

Similar articles


    1. Aizpurua-Olaizola O., Elezgarai I., Rico-Barrio I., Zarandona I., Etxebarria N., Usobiaga A. (2017). Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov. Today 22, 105–110. 10.1016/j.drudis.2016.08.005 – DOI PubMed
    1. Akopian A. N., Ruparel N. B., Jeske N. A., Patwardhan A., Hargreaves K. M. (2009). Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol. Sci. 30, 79–84. 10.1016/ – DOI PMC PubMed
    1. Bandell M., Dubin A. E., Petrus M. J., Orth A., Mathur J., Sun W. H., et al. . (2006). High-throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol. Nat. Neurosci. 9, 493–500. 10.1038/nn1665 – DOI PubMed
    1. Bautista D. M., Movahed P., Hinman A., Axelsson H. E., Sterner O., Högestätt E. D., et al. . (2005). Pungent products from garlic activate the sensory ion channel TRPA1. Proc. Natl. Acad. Sci. U.S.A. 102, 12248–12252. 10.1073/pnas.0505356102 – DOI PMC PubMed
    1. Bender F. L., Mederos Schnitzler M., Li Y., Ji A., Weihe E., Gudermann T., et al. . (2005). The temperature-sensitive ion channel tRPV2 is endogenously expressed and functional in the primary sensory cell line F-11. Cell. Physiol. Biochem. 15, 183–194. 10.1159/000083651 – DOI PubMed



error: Content is protected !!
%d blogueurs aiment cette page :