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

Abstract

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.

Repurposing Cannabidiol as a Potential Drug Candidate for Anti-Tumor Therapies

“…In contrast to TRPV1, TRPV2 is predominantly activated by different phytocannabinoids [ 50 ] including CBD [ 51 ]. The efficacy of CBD to activate TRPV3/4 is weaker compared to that of TRPV1/2 (~54, ~15 vs. ~78, ~67%, respectively) [ 52 ] ( Table 1 ). CBD displays a high potency to agonistically support the TRP ankyrin type-1 (TRPA1) channel’s activity (efficacy ~108%) [ 52 ], whereas it antagonizes the TRP melastatin type-8 (TRPM8) channel’s activity [ 53 ].…”

“…The efficacy of CBD to activate TRPV3/4 is weaker compared to that of TRPV1/2 (~54, ~15 vs. ~78, ~67%, respectively) [ 52 ] ( Table 1 ). CBD displays a high potency to agonistically support the TRP ankyrin type-1 (TRPA1) channel’s activity (efficacy ~108%) [ 52 ], whereas it antagonizes the TRP melastatin type-8 (TRPM8) channel’s activity [ 53 ]. Other molecular targets of CBD that are mediated through the CB1/CB2 receptors include the fatty acid neurotransmitter [ 54 , 55 , 56 ], G-protein coupled receptors (GPR55/ GPR18) [ 57 , 58 , 59 , 60 ], serotonin receptor 5-HT1 [ 61 ], peroxisome proliferator-activated receptor γ (PPARγ) [ 62 , 63 ], cyclooxygenase-2 (COX-2) enzymes and glycine-receptor [ 64 ].…”

Endocannabinoids produced in photoreceptor cells in response to light activate Drosophila TRP channels

“…Moreover, at least six mammalian TRP channels are activated in vitro by cannabinoids and endocannabinoids, including four TRPV channels, TRPA1, and TRPM8 ( 57 , 58 ). An interaction between rat TRPV2 and cannabidiol was identified in a cryo–electron microscopy structure ( 59 ), and differences in the putative binding sites among mammalian TRP channels have been modeled and discussed ( 60 , 61 ). Similarly, the Drosophila TRPC channels TRP and TRPL may also be receptors for endocannabinoids.…”

Vapor exposure to Δ9-tetrahydrocannabinol (THC) slows locomotion of the Maine Lobster (Homarus americanus)

“…THC appears to function as a ligand at TRPV2, TRPV3, TRPV4, TRPA1, and TRPV8, as reviewed (Muller et al, 2019; Starkus et al, 2019), and the Caribbean spiny lobster ( Panulirus argus ) expresses 17 TRP channels including TRPA and TRPV homologs (Kozma et al, 2020). A further clue is provided by the fact that another cannabis constituent which does not have substantial activity at endocannabinoid receptors (Boggs et al, 2018), cannabidiol (CBD), also had inhibitory effects in Turkanis and Karler (1988), and CBD modulates several THC sensitive TRPs (Muller and Reggio, 2020; Starkus et al, 2019). One apparent concern for this interpretation is that mammal TRPA1 is activated by noxious low, but not high, temperature.…”