The effects of vanilloid analogues structurally related to capsaicin on the transient receptor potential vanilloid 1 channel

Y Oka; K Takahashi; T Ohta

doi:10.1016/j.bbrep.2022.101243

The effects of vanilloid analogues structurally related to capsaicin on the transient receptor potential vanilloid 1 channel

Biochem Biophys Rep. 2022 Mar 8:30:101243. doi: 10.1016/j.bbrep.2022.101243. eCollection 2022 Jul.

Authors

Y Oka¹, K Takahashi^{1

2}, T Ohta^{1

2}

Affiliations

¹ Department of Veterinary Pharmacology, Faculty of Agriculture, Tottori University, Tottori, Japan.
² Joint Graduate School of Veterinary Sciences, Gifu University, Tottori University, Tottori, Japan.

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is known as a receptor of capsaicin, a spicy ingredient of chili peppers. It is also sensitive to a variety of pungent compounds and is involved in nociception. Here, we focused on the structural characteristics of capsaicin, and investigated whether vanillylmanderic acid (VMA), vanillic acid (VAcid), vanillyl alcohol (VAlc), vanillyl butyl ether (VBE), and vanillin, containing a vanillyl skeleton similar to capsaicin, affected the TRPV1 activities. For detection of TRPV1 activity, intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured in HEK 293 cells heterologously expressing mouse TRPV1 (mTRPV1-HEK) and in mouse sensory neurons. Except for vanillin, four vanilloid analogues dose-dependently increased [Ca²⁺]_i in mTRPV1-HEK. The solutions that dissolved VMA, VAcid and vanillin at high concentrations were acidic, whereas those of VAlc and VBE were neutral. Neutralized VAcid evoked [Ca²⁺]_i increases but neutralized VMA did not. Mutation of capsaicin-sensing sites diminished [Ca²⁺]_i responses to VAcid, VAlc and VBE. VAcid, VMA, and vanillin suppressed the activation of TRPV1 induced by capsaicin. VAcid and VMA also inhibited the acid-induced TRPV1 activation. In sensory neurons, VMA diminished TRPV1 activation by capsaicin or acids. The present data indicate that these structural characteristics of chemical compounds on TRPV1 may provide strategies for the development of novel analgesic drugs targeting nociceptive TRPV1.

Keywords: Catecholamine metabolites; DMSO, Dimethyl sulfoxide; DRG, Dorsal root ganglion; HEK, Human embryonic kidney; Heterologous expression; Intracellular Ca2+ concentration; Mutagenesis; Sensory neurons; TRPV, Transient receptor potential vanilloid 1; VAcid, Vanillic acid; VBE, Vanillyl butyl ether; VMA, Vanillylmandelic acid; Valc, Vanillyl alcohol; Vanillyl structure; [Ca2+], Intracellular Ca2+ concentration; mTRPV1, Mouse TRPV1.