Abstract

Members of the transient receptor potential (TRP) family of nonselective cation channels are involved in several pathological and physiological conditions. The search for the molecular targets for naturally occurring substances, especially from plants, allowed the characterization of many TRP channels. In fact, attempts to understand the hot and painful action of the vanillyl group containing compounds capsaicin (from Capsicum sp.) and its ultrapotent analogue resiniferatoxin (RTX, from Euphorbia sp.) led to the cloning of the vanilloid receptor (TRPV1) 7 years ago. TRPV1 is found in sensory fibers and functions as a molecular integrator of several painful stimuli, being especially stimulated during inflammation. Since TRPV1 is involved in several pathological conditions, selective ligands or modulators of this channel are substances of potential interest to treat such diseases. Once again, natural products seem to be also interesting sources of compounds that might be prototype TRPV1 ligands. The cloning of TRPV1 also enabled the discovery of other members of the TRPV family of channels. Similar to TRPV1, these receptors function as molecular detectors of physical and chemical stimuli, such as innocuous and noxious heat, as well as mechanical force. Recently, novel TRP channels sensitive to low temperatures also have been cloned, namely, TRPM8 and TRPA1. Such channels are also activated by naturally occurring substances but knowledge of their involvement in health and disease is in its infancy. In the present review, we focused on the contribution of natural products to the discovery of TRP channels and to the development of novel drugs to treat pathological conditions in which these channels are involved.

Keywords: Natural products; Capsaicin; Resiniferatoxin; TRPV1; TRPM8; TRPA1

Abbreviations: ANKTM, ankyrin-like protein with transmembrane; ATP, adenosine triphosphate; Ca²⁺, calcium; cDNA, complementary deoxyribonucleic acid; CGRP, calcitonin gene-related peptide; CHO cells, Chinese hamster ovary cells; COX, cyclooxygenase; DAG, diacylglycerol; DRG, dorsal root ganglion; HEK cells, human embryonic kidney cells; hTRP, human TRP; IP₃, inositol trisphosphate; LOX, lipoxygenase; mRNA, messenger ribonucleic acid; mTRP, mouse TRP; nAchR, nicotinic acetylcholine receptors; NGF, nerve growth factor; P2Y, purine receptor; PGE₂, prostaglandin E₂; PIP₂, phosphatidylinositol bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLA₂, phospholipase A₂; PLC, phospholipase C; rTRP, rat TRP; RTX, resiniferatoxin; THC, Δ⁹-tetrahydrocannabinol; TG, trigeminal ganglion; TM, transmembrane; TRP, transient receptor potential

Article Outline

1. Introduction

1.1. Family of transient receptor potential channels

2. TRPV1

2.1. Historical use and isolation of pungent ingredient in Capsicum sp.

2.2. Capsaicin as a selective activator of nociceptors

2.3. Resiniferatoxin and the early characterization of a receptor for capsaicin

2.4. Cloning of the vanilloid receptor

2.5. Differential sensitivities to capsaicin among animal species: why Capsicum produces capsaicin and where ligand-binding sites are on TRPV1

2.6. Endogenous lipid ligands for TRPV1

2.7. The expression of TRPV1 in sensory neurons and other tissues

2.8. Development of mice lacking the TRPV1

2.9. TRPV1 regulation and activation

2.10. Involvement of TRPV1 in pathological conditions

2.11. Other naturally occurring TRPV1 ligands

2.11.1. Capsaicinoids and capsaicin-related compounds

2.11.1.1. Capsiate

2.11.1.2. Piperine

2.11.1.3. Eugenol

2.11.2. Ginger-derived products

2.11.2.1. Shogaol and gingerols

2.11.2.2. Zingerone

2.11.2.3. Paradol

2.11.3. Fatty acids

2.11.4. Ginsenosides

2.11.5. Cannabinoid

2.11.6. Evodia compounds

2.11.7. Unsaturated 1,4-dialdehydes terpenes

2.11.7.1. Polygodial and drimanial

2.11.7.2. Isovelleral

2.11.7.3. Other unsaturated 1,4-dialdehydes terpenes

2.11.8. Triprenyl phenols

2.11.9. Other candidates for the modulation of TRPV1

2.11.9.1. Thapsigargin

2.11.9.2. Guaiacol

2.11.9.3. Nicotine

2.11.9.4. Yohimbine

2.12. Final considerations for TRPV1

3. New members of the vanilloid receptor transient receptor potential family

4. Cold-sensitive transient receptor potentials

4.1. The sensations of cool and cold

4.2. TRPM8 is a cold sensor in the long, melastatin transient receptor potential subfamily

4.2.1. Characterization of TRPM8 as a cold-sensitive channel

4.2.2. The importance of menthol in TRPM8 characterization

4.2.3. Other natural or synthetic substances that stimulate TRPM8

4.2.3.1. Eucalytol

4.2.3.2. Other monoterpenes

4.2.3.3. Eugenol

4.2.3.4. Synthetic products

4.2.4. Role of TRPM8 in specific nociceptive processes

4.3. TRPA1, a member of the new ankyrin-repeat transient receptor potential channel family

4.3.1. TRPA1 is expressed in subsets of sensory neurons

4.3.2. Modulation of TRPA1 by stimulation of agonist-coupled receptors

4.3.3. TRPA1 is activated by several natural products

4.3.3.1. Isothiocyanate compounds

4.3.3.2. Cinnamaldehyde

4.3.3.3. Δ⁹-tetrahydrocannabinol

4.3.3.4. Other natural products are nonspecific TRPA1 activators

4.3.4. TRPA1 is a potential target for the development of new analgesic drugs

5. Final considerations

Acknowledgements

References