Trp Channels

Let us first take a look at TrpV1, perhaps the best studied member of this family. The following image was adapted from [1] and from the online protein data bank Trp channels have four subunits. They are colored red, orange, blue, and cyan in this image. The mode of viewing is “surface” or what a water molecule sees.The top view looking down is what an ion from the outside of the cell sees. The opening is only an indentation in the center. The channel is sort of bell shaped with the widest part inside the cell. The gray structure is the channel cavity. It has two bottle necks. The one on the outside of the cell is the ion selectivity filter. It allows mostly Ca2+ and some Na+. It keeps out Cl, K+ and other ions. The second bottleneck is the “gate.” The active compound in chili peppers, capsaicin, opens this gate. Y513 is a single letter amino acid code for tyrosine, the 513th amino acid in the TrpV1 protein. In this image we have S3, S5, and S6. The are three of the six membrane spanning helices that compose each of the four subunits of the Trp family of channels. Just a general note on reference [1]: The Cap domain is cap as in bottle cap, not capsaicin. The cap domain and the capsaicin binding site are connected.

Cannabinoids gating the Trp chanels

Dr Patricia Reggio and coauthors published a review on their work with cannabinoids on the Trp family of Ca2+ channels. Much of their work involved Human Embryonic Kidney cells HEK-293. [2]


outward rectification means a current of negative charges current flows more easily to the outside of the cell. … or in the case of positive charges more easily to the inside of the cell.

Efficacy was measured as % 4 μM ionomycin, a Ca2+ ionophore. Ionomycin allows Ca2+ to pass from the extracellular compartment to the inside of the cell just like the Trp channels.

Potency is the effective concentration to achieve 50% of maximum activity, or EC50.

Desensitization is the process by which a channel becomes refractory to further stimuli after a period of activity. [1] Capsaicin creams used to shut off the TrpV1 channel. Densitization by endo and phyto cannabinoids was measured as how much was required to make the channel refractory to 0.1 μM capsaicin for TrpV1. [2]

Intro to some Trp family members

Most of this information comes from and The basic schematic of these channels are from reference [2]. Exceptions are given by the PubMed identifier number. It is easy to be overwhelmed by the complexity. The take home that no matter how much we learn, there is a lot we do not understand.


is known for being gated by capsaicin of hot peppers, temperatures >45oC temperatures. “Predominantly expressed in trigeminal and dorsal root sensory ganglia. Expressed also in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain. High expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex. In the brain detected also in astrocytes and pericytes (at protein level). Isoform 1 and isoform 3 are expressed in brain and peripheral blood mononuclear cells” The C-terminus contains sites for calmodulin and PIP2. βg subunit mediated activation of phospholipase C cleaves the IP3 head group form PIP2 that opens calcium stores. Ca2+ binds to calmodulin. Model agonist: 0.1 μM capsaicin.[2]

TrpV1 Going from the N terminus (Nter) (TrpV1 is expressed in the brain and gastrointestinal system (Protein Atlas). ATP binds to the Ankyrin Repeat Domains (ARD,red ovals) There are also some protein kinase A (PKA) phosphorylation sites in the ARD. 20-hydroxyeicosatetraenoic acid (20-HETE) binds around he 2nd transmembrane helix. capsaicin binds to residues Y512, S513, T551, and E571. Note the structural similarity with CBD.. The peptide hormone oxytocin interacts with residues E600, G602, Y631, and L635 [2] The brain expression is rather non specigic. (Protein Atlas) lysophosphatidic acid (LPA) binds to the K710.

Ca2+-calmodulin also binds to the N-terminus near the ATP site. See turning TrpA1 off for a very brief overview.


This outwardly rectifying that opens in response to temperatures greater than 52oC. Vanilloids like capsaicin and low pH do not gate this channel. Model agonist: 3 μM lysophosphatidylcholine at IC50 concentrations. [1]


is opened by moderately warm temperatures. Temperatures above 39oC show an increased response, “Abundantly expressed in CNS. Widely expressed at low levels. Detected in dorsal root ganglion (at protein level). Expressed in the keratinocyte layers of the outer root sheath and, to lesser extent, to the matrix of the hair follicles (at protein level)” Protein Atlas lists TrpV3 mRNA content by cell type. The top four are the following: suprabasal keratinocytes> basal keratinocytes > enterocytes > Melanocytes. Model agonist: 3 μM carvacol at IC50 concentrations.


is regulated by mechanical stimulation and osmotic changes in which the changes in osmotic pressure have the same effect as mechanical stimuli. This isoform has ATP and PIP2 sites in the N-terminal cytoplasmic domain. According to the human brain mRNA consensus map available from, TrpV4 is expressed in the medulla/pons and the hippocampus. According to ProteinAtlas, TrpV4 levels are higher in neuronal cells than glia. A recent study demonstrated this action is due to phospholipase A2. PLA2 cleaves arachidonic acid from the SN-2 position of membrane phospholipids. Model agonist: phorbol ester at IC50 concentrations.


responds to noxious stimuli such as allylthiocyanate (AITC) from mustard oil or wasabi, cinnamaldehyde, diallyl disulfide (DADS) from garlic, and acrolein. Wasabi and other noxious compounds bind to the N-terminal cytoplasmic domain. TRPA1 activation by electrophiles occurs though covalent modification of specific cysteine residues in the N-terminal cytoplasmic domain. Hydroxylation is required for TRPA1 activity inhibition in normoxia. In hypoxia, the decrease in oxygen concentration diminishes the activity of the hydroxylase EGLN1, thus relieving TRPA1 from inhibition and ultimately leading to channel activation. This channel is also gated by 9-THC Model agonist: 100 μM allyl isothiocyanate. [2]


is the menthol (cool mint) receptor as well as temperatures <25oC. Eucalyptal and ilicin are also ligands. Several years ago I wrote about peppermint oil for IBS. (irritable bowel syndrome) Add the peppermint oil terpene pugelone to the list! TrpM8 mRNA expression can be detected in the cerebral cortex, thalamus, basal ganglia, and pons/medulla, but not enough to color the brain diagram pink! TrpM8 has to be more important than limited expression data would suggest. FDA is banning menthol in cigarettes due to addictive and analgesic potential in addition to the kid appeal. Rosario González-Muñiz and coauthors from the Instituto de Química Médica in Madrid, Spain have written a review on natural and synthtic agonists and antagonist of TrpM8. [3] Eucalyptol and borneol are listed as agonists. Cannabidivarin is an antagonist. [3] Model agonist: 50 μM menthol.

TrpM8 information came froem,,, PubMed, and reference [1]
CompoundEfficacy* (μM)Potency EC50 (μM)Desensitization (μM)
TrpV12-AG59.1 ± 0.30.85 ± 0.060.75 ± 0.03
AEA53.8 ± 0.20.27 ± 0.010.21 ± 0.06
CBD44.7 ± 0.021.0 ± 0.10.6 ± 0.05
CBD40.5 ± 1.61.25 ± 0.234.5 ± 0.7
THC53.0 ± 1.40.65 ± 0.050.8 ± 0.1
TrpV3CBD50.1 ± 4.83.7 ± 1.60.9 ± 0.3
TrpA1AEA158.7 ± 11.110.1 ± 1.921.0 ± 1.6
CBD115.9 ± 4.60.11 ± 0.050.16 ± 0.05
THC117 ± 120.23 ± 0.03
TrpM8AEA3.09 ± 0.61
vs mentholTHC0.15 ± 0.02

What does this mean for a physician?

TrpA1 and TrpM8 have been implicated in head aches and migraines. {4] So TrpM8 is the origin of the ice cream head ache? TrpA1, the oxidative stress Trp family member makes a strong case for migraine coming from the usual source of thio reactive super oxide: high rate of energy production by the mitochondria, damage to the mitochondria, calcium overload and excitotoxicity, neuroinflammation, reactive strocytes, and NADPH oxidase, and monoamine oxidase. [5] or cytochrome P450 processing, or from uncoupling of nitric oxide synthase Miss Marijuana lists Belladona as the #1 strain for migraines. Belladona is 18% THC and 1% CBG with myrcene the dominant terpene according to Leafly lists Harlequin as only 5% THC and 9% CBD. Myrcene is the dominant terpene. This site will review myrcene and terpene TrpV1 regulation and bring in TrpA1. A publication that showed lack of terpene/cannabinoid entourage effects in a cell culture system. Cinnaminaldehyde was used as an agonist, but thiol reduction was not. Is it good for the patient if beta-mercene has no effect if TrpA1 has not been activated by some oxidative stress event?


  1. Nadezhdin, K. D., Neuberger, A., Nikolaev, Y. A., Murphy, L. A., Gracheva, E. O., Bagriantsev, S. N., & Sobolevsky, A. I. (2021). Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nature communications, 12(1), 2154. PMC free article
  2. Muller, C., Morales, P., & Reggio, P. H. (2019). Cannabinoid Ligands Targeting TRP Channels. Frontiers in molecular neuroscience, 11, 487. PMC free article
  3. González-Muñiz, R., Bonache, M. A., Martín-Escura, C., & Gómez-Monterrey, I. (2019). Recent Progress in TRPM8 Modulation: An Update. International journal of molecular sciences, 20(11), 2618. ,,PMC free article
  4. Moore, C., Gupta, R., Jordt, S. E., Chen, Y., & Liedtke, W. B. (2018). Regulation of Pain and Itch by TRP Channels. Neuroscience bulletin, 34(1), 120–142. PMC free article
  5. Borkum JM. (2016) Migraine Triggers and Oxidative Stress: A Narrative Review and Synthesis. Headache. 2016 Jan;56(1):12-35. PMC free article
  6. Baron, E. P., Lucas, P., Eades, J., & Hogue, O. (2018). Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. The journal of headache and pain, 19(1), 37. PMC free article

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