The Molecular Basis for Species-specific Activation of Human TRPA1 Protein by Protons Involves Poorly Conserved Residues within Transmembrane Domains 5 and 6

Roche, J; Eberhardt, Mirjam; Klinger, Alexandra B.; Stanslowsky, Nancy; Wegner, Florian; Koppert, Wolfgang; Reeh, Peter W.; Lampert, Angelika; Fischer, Michael J.M.; Leffler, Andreas

doi:10.1074/jbc.m113.479337

Cited by 89 publications

(77 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, cold activates rodent, but not human or monkey, TRPA1 . Furthermore, hTRPA1 acts as a sensor for tissue acidosis, whereas protons, conversely, inhibit rTRPA1 (de la Roche et al, 2013). This might have given false negative results when testing TRPA1 antagonists as potential analgesic agents in rodent models of cancer-induced bone pain, in which the acidic microenvironment is believed to be an important contributor to pain (Lozano-Ondoua et al, 2013).…”

Section: Transient Receptor Potential Channels: Acquired Diseasesmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

View full text Add to dashboard Cite

Section: Transient Receptor Potential Channels: Acquired Diseasesmentioning

confidence: 99%

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

2014

View full text Add to dashboard Cite

“…Protons activate and sensitize human TRPA1 but inhibit mouse TRPA1. At least two amino acid residues (valine 942 and serine 943) located in TM5 and TM6 are involved in this species specificity for the effects of protons (41). Thus, slight differences in the amino acid residues on TRPA1 channels among various animal species might result in unexpected effects.…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis Determining Inhibition/Activation of Nociceptive Receptor TRPA1 Protein

Banzawa

Saito

Imagawa

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Nociceptive TRPA1 is an important drug discovery target for identification of analgesics. Results: A967079, one of the most potent mammalian TRPA1 antagonists, showed marked species differences. Conclusion: A single amino acid was responsible for inhibitory/stimulatory actions of A967079. Significance: The present data provide novel insight in the search for analgesics targeting TRPA1.

show abstract

“…5 M capsaicin and 500 M muralatin L were added at the indicated time points. Data were averaged from capsaicin-sensitive cells in the field (18,19). Cells were imaged under Olympus IX81 microscope.…”

Section: Methodsmentioning

confidence: 99%

Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata

Wang

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay-guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy.Murraya is a popular genus of flowering plants in the Rutaceae family known for their specific fragrance. Most plants from this genus have been used as traditional Chinese medicines for treating psychogenic pain or somatoform pain disorders, including toothache, gastralgia, lumbago, rheumatic pain, etc. (1). Previous phytochemical and pharmacological investigations have shown that coumarins isolated from Murraya plants are the main bioactive agents responsible for analgesic properties of these medicinal herbs (2). However, the bioactive ingredients have always been a riddle, and their mechanisms of action remain largely unknown.The transient receptor potential vanilloid member 1 (TRPV1) channel, also known as capsaicin receptor, is a nonselective cation and heat-activated channel with a temperature threshold above 43°C (3). In addition to chili pepper and temperature, TRPV1 is also activated by acidic pH, and a plethora of other chemicals from plants and toxins (3-7). TRPV1 belongs to the TRPV 4 subfamily that is composed of six members divided into two groups as follows: TRPV1-4 channels that are modestly permeable to Ca 2ϩ , and TRPV5-6 channels that are only highly Ca 2ϩ -selective, based on their homology and biophysical properties (8, 9). The expression of TRPV1 has been primarily demonstrated in pain pathways, including small diameter primary sensory neurons (10) and keratinocytes in the skin where it plays a key role in nociception induced by capsaicin or noxious thermal stimuli (11,12). Mice lacking Trpv1 show dramatic reduction of pain...

show abstract

The Molecular Basis for Species-specific Activation of Human TRPA1 Protein by Protons Involves Poorly Conserved Residues within Transmembrane Domains 5 and 6

Cited by 89 publications

References 53 publications

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Molecular Basis Determining Inhibition/Activation of Nociceptive Receptor TRPA1 Protein

Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata

Contact Info

Product

Resources

About