Transient receptor potential channels as targets for phytochemicals

Abstract

To date, 28 mammalian transient receptor potential (TRP) channels have been cloned and characterized. They are grouped into six subfamilies on the basis of their amino acid sequence homology: TRP Ankyrin (TRPA), TRP Canonical (TRPC), TRP Melastatin (TRPM), TRP Mucolipin (TRPML), TRP Polycystin (TRPP), and TRP Vanilloid (TRPV). Most of the TRP channels are nonselective cation channels expressed on the cell membrane and exhibit variable permeability ratios for Ca(2+) versus Na(+). They mediate sensory functions (such as vision, nociception, taste transduction, temperature sensation, and pheromone signaling) and homeostatic functions (such as divalent cation flux, hormone release, and osmoregulation). Significant progress has been made in our understanding of the specific roles of these TRP channels and their activation mechanisms. In this Review, the emphasis will be on the activation of TRP channels by phytochemicals that are claimed to exert health benefits. Recent findings complement the anecdotal evidence that some of these phytochemicals have specific receptors and the activation of which is responsible for the physiological effects. Now, the targets for these phytochemicals are being unveiled; a specific hypothesis can be proposed and tested experimentally to infer a scientific validity of the claims of the health benefits. The broader and pressing issues that have to be addressed are related to the quantities of the active ingredients in a given preparation, their bioavailability, metabolism, adverse effects, excretion, and systemic versus local effects.

Keywords: TRP channel; botanical; neuropeptide; phytochemical.

Figure 1

TRPA1 agonists (phytochemicals, synthetic chemicals, and endogenous molecules). Allicin, 2-propene-1-sulfinothioic acid S-2-propenyl ester; allylisothiocyanate (AITC), 3-isothiocyanato-1-propene, is an organosulfur compound; cinnamaldehyde, (2E)-3-phenylprop-2-enal; Δ⁹-tetrahydrocannabinol, (−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol; umbellulone, 1-isopropyl-4-methylbicyclo[3.1.0]hex-3-en-2-one; ligustilide, (3Z)-3-butylidene-4,5-dihydro-2-benzofuran-1(3H)-one; methyl salicylate, methyl 2-hydroxybenzoate; icilin, 1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one; N-methylmaleimide (oxidizing agent); 4-hydroxynonenal, 4-hydroxy-2-nonenal, an α,β-unsaturated hydroxyalkenal produced by lipid peroxidation, is an endogenous agonist; methylglyoxal, an aldehyde from pyruvic acid, acts both as an aldehyde and ketone, and reacts with free amino acids such as lysine, arginine and thiol groups of cysteine. MG is an endogenous agonist.

Figure 2

Other TRP channel activators. Hyperforin, (1R,5S,6R,7S)-4-hydroxy-5-isobutyryl-6-methyl-1,3,7-tris(3-methyl-2-buten-1-yl)-6-(4-methyl-3-penten-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione (TRPC6); bisandrographolide, 3-{(E)-2-[6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydro-1-naphthalenyl]vinyl}-5-{6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylene-1-[2-(2-oxo-2,5-dihydro-3-furanyl)ethyl]decahydro-1-naphthalenyl}-2(5H)-furanone (TRPV4); paclitaxel, (2α,5β,7β,10β,13α)-4,10-diacetoxy-13-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate (TRPA1, TRPV4); dicentrine, (7aS)-10,11-dimethoxy-7-methyl-6,7,7a,8-tetrahydro-5H-[1,3]benzodioxolo[6,5,4-de]benzo[g]quinoline (TRPA1).

Figure 3

TRPM8 agonists. Menthol, (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol; eucalyptol, 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; icilin, 1-(2-hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one.

Figure 4

TRPV1 agonists. Vanillin, has the vanillyl moiety, that is essential for activating TRPV1 channels; Capsaicin, (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonenamide, has a vanilloid and an aceyl moiety; dihydrocapsaicin, the structure of which is a 6,7-dihydro derivative of capsaicin; resiniferatoxin, has a complex structure, but shares a homovanillyl group, which is necessary for the activity of all vanilloids; eugenol, 2-methoxy-4-(2-propenyl)phenol and is a member of the allylbenzene class of chemical compounds; Cannabidiol, 2-[(1R,6R)-6-isopropenyl-3-methyl-3-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; anandamide or arachidonylethanolamide or arachidonic acid N-(hydroxyethyl)amide consists of the acyl moiety and is an edogenous ligand of TRPV1 and cannabinoid receptor 1 (CB1).