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Review
. 2019 Jan 15:11:487.
doi: 10.3389/fnmol.2018.00487. eCollection 2018.

Cannabinoid Ligands Targeting TRP Channels

Chanté Muller  1 , Paula Morales  1 , Patricia H Reggio  1
Affiliations
Review

Cannabinoid Ligands Targeting TRP Channels

Chanté Muller et al. Front Mol Neurosci. .

Abstract

Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be "ionotropic cannabinoid receptors." Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, N-arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ9-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.

Keywords: TRP channels; TRPA1; TRPM8; TRPV1; cannabidiol; cannabinoids.

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Figures

Figure 1
Figure 1
General topology of the transient receptor potential (TRP) channels discussed in this review: TRPV1–4, TRPA1 and TRPM8.
Figure 2
Figure 2
The lipid view of TRPV1 adapted from PDB: 3J5P. Ankyrin repeat domain (ARD) shown in red, transmembrane helices shown in yellow, TRP domain shown in purple, and intracellular regions (ICRs) and extracellular regions (ECRs) shown in green. Sections have been omitted for clarity.
Figure 3
Figure 3
(A) The lipid view of TRPA1 adapted from PDB: 3J9P. ARD shown in red, transmembrane region (TMR) shown in yellow, TRP-like domain shown in purple, ICRs- and ECRs shown in green and coiled-coil shown in pink. Sections have been omitted for clarity. (B) The intracellular view of TRPA1 adapted from PDB: 3J9P. Coiled-coil shown in pink. Sections have been omitted for clarity.
Figure 4
Figure 4
Structure of selected endocannabinoids that target TRP channels.
Figure 5
Figure 5
Structure of selected plant cannabinoid ligands that target TRP channels.
Figure 6
Figure 6
Structure of selected synthetic cannabinoid ligands that target TRP channels: (A) aminoalkyindole derivatives; (B) arylpyrazole derivatives; (C) synthetic phytocannabinoids analogs.
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