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Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1.
Mol Pharmacol. 2014 Feb; 85(2):335-44.MP

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective ligand-gated cation channel responding to noxious heat, protons, and chemicals such as capsaicin. TRPV1 is expressed in sensory neurons and plays a critical role in pain associated with tissue injury, inflammation, and nerve lesions. Transient receptor potential ankyrin 1 (TRPA1) is coexpressed with TRPV1. It is activated by compounds that cause a burning sensation (e.g., mustard oil) and, indirectly, by components of the inflammatory milieu eliciting nociceptor excitation and pain hypersensitivity. Previous studies indicate an interaction of TRPV1 and TRPA1 signaling pathways. Here we sought to examine the molecular mechanisms underlying such interactions in nociceptive neurons. We first excluded physical interactions of both channels using radioligand binding studies. By microfluorimetry, electrophysiological experiments, cAMP measurements, and site-directed mutagenesis we found a sensitization of TRPV1 after TRPA1 stimulation with mustard oil in a calcium and cAMP/protein kinase A (PKA)-dependent manner. TRPA1 stimulation enhanced TRPV1 phosphorylation via the putative PKA phosphorylation site serine 116. We also detected calcium-sensitive increased TRPV1 activity after TRPA1 activation in dorsal root ganglion neurons. The inhibition of TRPA1 by HC-030031 (1,2,3,6-tetrahydro-1,3-dimethyl-N-[4-(1-methylethyl)phenyl]-2,6-dioxo-7H-purine-7-acetamide, 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide) after its initial stimulation (and the calcium-insensitive TRPA1 mutant D477A) still showed increased capsaicin-induced TRPV1 activity. This excludes a calcium-induced additive TRPA1 current after TRPV1 stimulation. Our study shows sensitization of TRPV1 via activation of TRPA1, which involves adenylyl cyclase, increased cAMP, subsequent translocation and activation of PKA, and phosphorylation of TRPV1 at PKA phosphorylation residues. This suggests that cross-sensitization of TRP channels contributes to enhanced pain sensitivity in inflamed tissues.

Authors+Show Affiliations

Charité, Universitätsmedizin Berlin, Klinik für Anästhesiologie und Operative Intensivmedizin, Berlin, Germany (V.S., C.S., C.Z.); and Universitätsklinikum Hamburg, Eppendorf, Klinik und Poliklinik für Anästhesiologie, Zentrum für Anästhesiologie und Intensivmedizin, Hamburg, Germany (C.Z.).No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24275229

Citation

Spahn, Viola, et al. "Modulation of Transient Receptor Vanilloid 1 Activity By Transient Receptor Potential Ankyrin 1." Molecular Pharmacology, vol. 85, no. 2, 2014, pp. 335-44.
Spahn V, Stein C, Zöllner C. Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1. Mol Pharmacol. 2014;85(2):335-44.
Spahn, V., Stein, C., & Zöllner, C. (2014). Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1. Molecular Pharmacology, 85(2), 335-44. https://doi.org/10.1124/mol.113.088997
Spahn V, Stein C, Zöllner C. Modulation of Transient Receptor Vanilloid 1 Activity By Transient Receptor Potential Ankyrin 1. Mol Pharmacol. 2014;85(2):335-44. PubMed PMID: 24275229.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of transient receptor vanilloid 1 activity by transient receptor potential ankyrin 1. AU - Spahn,Viola, AU - Stein,Christoph, AU - Zöllner,Christian, Y1 - 2013/11/25/ PY - 2013/11/27/entrez PY - 2013/11/28/pubmed PY - 2014/2/19/medline SP - 335 EP - 44 JF - Molecular pharmacology JO - Mol Pharmacol VL - 85 IS - 2 N2 - Transient receptor potential vanilloid 1 (TRPV1) is a nonselective ligand-gated cation channel responding to noxious heat, protons, and chemicals such as capsaicin. TRPV1 is expressed in sensory neurons and plays a critical role in pain associated with tissue injury, inflammation, and nerve lesions. Transient receptor potential ankyrin 1 (TRPA1) is coexpressed with TRPV1. It is activated by compounds that cause a burning sensation (e.g., mustard oil) and, indirectly, by components of the inflammatory milieu eliciting nociceptor excitation and pain hypersensitivity. Previous studies indicate an interaction of TRPV1 and TRPA1 signaling pathways. Here we sought to examine the molecular mechanisms underlying such interactions in nociceptive neurons. We first excluded physical interactions of both channels using radioligand binding studies. By microfluorimetry, electrophysiological experiments, cAMP measurements, and site-directed mutagenesis we found a sensitization of TRPV1 after TRPA1 stimulation with mustard oil in a calcium and cAMP/protein kinase A (PKA)-dependent manner. TRPA1 stimulation enhanced TRPV1 phosphorylation via the putative PKA phosphorylation site serine 116. We also detected calcium-sensitive increased TRPV1 activity after TRPA1 activation in dorsal root ganglion neurons. The inhibition of TRPA1 by HC-030031 (1,2,3,6-tetrahydro-1,3-dimethyl-N-[4-(1-methylethyl)phenyl]-2,6-dioxo-7H-purine-7-acetamide, 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide) after its initial stimulation (and the calcium-insensitive TRPA1 mutant D477A) still showed increased capsaicin-induced TRPV1 activity. This excludes a calcium-induced additive TRPA1 current after TRPV1 stimulation. Our study shows sensitization of TRPV1 via activation of TRPA1, which involves adenylyl cyclase, increased cAMP, subsequent translocation and activation of PKA, and phosphorylation of TRPV1 at PKA phosphorylation residues. This suggests that cross-sensitization of TRP channels contributes to enhanced pain sensitivity in inflamed tissues. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/24275229/Modulation_of_transient_receptor_vanilloid_1_activity_by_transient_receptor_potential_ankyrin_1_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=24275229 DB - PRIME DP - Unbound Medicine ER -