Associate editor: D. Spina
Biochemistry and pharmacology of endovanilloids

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Abstract

Endovanilloids are defined as endogenous ligands and activators of transient receptor potential (TRP) vanilloid type 1 (TRPV1) channels. The first endovanilloid to be identified was anandamide (AEA), previously discovered as an endogenous agonist of cannabinoid receptors. In fact, there are several similarities, in terms of opposing actions on the same intracellular signals, role in the same pathological conditions, and shared ligands and tissue distribution, between TRPV1 and cannabinoid CB1 receptors. After AEA and some of its congeners (the unsaturated long chain N-acylethanolamines), at least 2 other families of endogenous lipids have been suggested to act as endovanilloids: (i) unsaturated long chain N-acyldopamines and (ii) some lipoxygenase (LOX) metabolites of arachidonic acid (AA). Here we discuss the mechanisms for the regulation of the levels of the proposed endovanilloids, as well as their TRPV1-mediated pharmacological actions in vitro and in vivo. Furthermore, we outline the possible pathological conditions in which endovanilloids, acting at sometimes aberrantly expressed TRPV1 receptors, might play a role.

Introduction

The transient receptor potential (TRP) vanilloid type 1 (TRPV1) channel is a nonselective cation channel that belongs to the TRP family of proteins. TRP encompass at least 3 classes of ion channels that mediate the “receptor”-induced response of a cell to external “transient” stimuli, such as light, temperature, mechanical and osmotic stimuli, electrical charge, and xenobiotic substances, thereby increasing or decreasing its selective permeability to particular ions and subsequently modifying the cell membrane “potential.” In particular, TRP ion channels are named after the role of these proteins in the Drosophila phototransduction mutant that shows a transient instead of a sustained response to bright light (Montell, 2005). TRP are encoded by at least 21 channel subunit genes and are divided into 3 subfamilies: TRPC (canonical), TRPV (vanilloid), and TRPM (melastatin). The heat-activated TRPV1 (vanilloid receptor 1) was the first to be cloned among a group of 6 temperature-activated TRP ion channels (Caterina et al., 1997, Patapoutian et al., 2003). In fact, 4 heat-activated TRP channels (TRPV1–4) and 2 cold-activated channels (TRPM8 and TRPA1; Caterina and Julius, 2001, Patapoutian et al., 2003) have been identified to date. Repeated thermal stimulation may either evoke sensitization (TRPV3 and TRPV2) or desensitization (TRPV4 and TRPA1) of these receptors, as well as distinct intracellular signaling mechanisms within the family of TRP channels (for details, see Caterina et al., 1999, Guler et al., 2002, Peier et al., 2002, Smith et al., 2002, Watanabe et al., 2002, Xu et al., 2002, Story et al., 2003).

TRPV1 was first identified due to its responsiveness to the pungent compound capsaicin isolated from hot chili peppers. TRPV1 also responds to other plant toxins, the most potent of which is resiniferatoxin (RTX) (Szallasi & Blumberg, 1999), and to temperatures in the noxious range (> 43 °C) and acid (Caterina et al., 1997, Tominaga et al., 1998), suggesting that the “capsaicin receptor” may mediate both thermal and chemical pain. Consistent with the hypothesis of its involvement in pain and nociception, TRPV1 expression has been confirmed in small to medium diameter primary afferent fibers (Caterina et al., 1997), which are characteristic peptidergic sensory neurons of unmyelinated nociceptive Aδ and C fibers (Caterina et al., 1997, Tominaga et al., 1998). As mentioned above, TRPV1, being a nociceptor, can also become activated by low pH and inflammatory factors, such as nerve growth factor, bradykinin, lipids, prostaglandins, protein kinases A (PKA) and C (PKC), and ATP (Tominaga and Caterina, 2004, De Petrocellis and Di Marzo, 2005). Also non-neuronal cells, such as keratinocyes (Southall et al., 2003), bladder urothelium, and smooth muscle (Birder et al., 2001), liver (Reilly et al., 2003), polymorphonuclear granulocytes (Heiner et al., 2003), pancreatic β cells (Akiba et al., 2004), endothelial cells (Golech et al., 2004), lymphocytes (Saunders et al., 2007), and macrophages (Chen et al., 2003) express TRPV1, whose physiological role in these cells still remains to be fully understood. Interestingly, TRPV1 has been found also in the brain, such as in dopaminergic neurons of the substantia nigra, hippocampal pyramidal neurons, hypothalamic neurons, and neurons in the locus coeruleus and various layers of the cortex, where it might be involved in the modulation of synaptic plasticity (Mezey et al., 2000, Roberts et al., 2004). More recently TRPV1 has been localized in the rodent hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon, and hindbrain by means of immunohistochemistry (Toth et al., 2005, Cristino et al., 2006a), and its presence in several mouse brain areas was conclusively confirmed by the lack of immunoreactivity in the corresponding brain areas of TRPV1 null mice (Cristino et al., 2006a). The role of brain TRPV1 is not well defined and will be discussed below, although further studies are needed in order to establish its function. Recently, Kofalvi and colleagues (2006) reported no evidence for functional TRPV1 in rat hippocampal neurons, where inconsistent data between ex vivo and in vitro data on the neurochemical and physiological functions of TRPV1 were obtained. Others have recently reviewed the role of TRPV1 in the brain (Steenland et al., 2006).

In the central nervous system or under normal physiological conditions, TRPV1 is unlikely to be activated by heat or low pH. Therefore, the existence of endogenous ligands using this ion channel for inter- or intracellular signaling, the endovanilloids, was suggested (Di Marzo et al., 2001, van der Stelt and Di Marzo, 2004). The recognition of the chemical similarity between the endogenous ligand of cannabinoid receptors N-arachidonoyl-ethanolamine (anandamide, AEA) and capsaicin and, more remarkably, between potent N-acyl-vanillylamide agonists at vanilloid receptors and the prototypic inhibitor of AEA cellular uptake, AM404 (see below), marked the beginning of a large number of studies correlating the endocannabinoid and vanilloid signaling systems (Di Marzo et al., 1998a). Thus, AEA, first, (Zygmunt et al., 1999, Smart et al., 2000) and, later, other derivatives of long-chain unsaturated fatty acids, such as the N-acyldopamines (Huang et al., 2002, Chu et al., 2003), were shown to act as endogenous activators for TRPV1 (van der Stelt & Di Marzo, 2004) (Fig. 1). N-arachidonoyl-dopamine (NADA), but not its potential metabolite, O-methyl-NADA, was found to potently activate TRPV1 in the hippocampus (Huang et al., 2002). Other endogenous agonists of TRPV1 were described by Hwang et al. (2000), who reported that several products of lipoxygenases (LOX) were able to activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Of these compounds, 12-(S)-hydroperoxyeicosatetraenoic acid [12-(S)-HPETE], 15-(S)-hydroperoxyeicosatetraenoic acid [15-(S)-HPETE], and leukotriene B4 (LTB4) exhibited the highest efficacy.

In this article we review the current knowledge of (1) the regulation of the tissue levels of the endovanilloids and, hence, of the activity of their receptor targets, (2) their main pharmacological actions in vitro and in vivo, and (3) their potential physiological and pathological role.

Section snippets

Biosynthetic pathways for anandamide

AEA was originally isolated from porcine brain as the first endogenous cannabinoid (Devane et al., 1992), and its biosynthesis has subsequently been demonstrated in neurons (Di Marzo et al., 1994), macrophages (Di Marzo et al., 1996), and many other tissues and cell types. By activating the CB1 receptor, AEA reduces adenylate cyclase activity, inhibits the activity of voltage-gated Ca2+ currents and activates inwardly rectifying K+ currents (Mackie and Hille, 1992, Felder et al., 1993, Vogel et

Biosynthesis and degradation

NADA was identified as an endogenous compound that possesses medium to high nanomolar potency for both TRPV1 and cannabinoid CB1 receptors (Bisogno et al., 2000, Huang et al., 2002) and found at the highest concentrations (max, ∼ 6 pmol/g wet tissue weight) in 2 rat brain regions, the striatum and hippocampus. NADA was also found in cerebellum, thalamus, and DRG (Huang et al., 2002). Being most abundant in the striatum, the brain region with the highest amounts of DA, NADA was suggested to be

Anandamide and N-arachidonoyl-dopamine congeners as endovanilloids or “entourage” compounds

Among long-chain, linear fatty acid dopamides, also N-oleoyl-dopamine, was shown to potently activate TRPV1 (Chu et al., 2003). This compound was much more selective than NADA versus CB1 receptors. Two other congeners, N-palmitoyl- and N-stearoyl-dopamine (PALDA and STEARDA), though inactive per se on TRPV1, acted, in both HEK293 cells overexpressing the human TRPV1 and in in vivo experiments, as ‘entourage’ compounds, that is, they enhanced the stimulatory effects on TRPV1 exerted by other

Biosynthesis and degradation

In addition to AEA, NADA, and their congeners, also LOX products of AA have been proposed as candidates for the role of endovanilloids. 12-(S)-HPETE, 15-(S)-HPETE, and LTB4 were shown to be more efficacious than AEA as vanilloid receptor agonists when monitoring TRPV1-mediated currents in isolated membrane patches of sensory neurons and in HEK cells (Hwang et al., 2000). The structural similarity between capsaicin and 12-(S)-HPETE was demonstrated by modelling studies and might explain why

3-Hydroxy-eicosatetraenoic acid and 3-hydroxy-anandamide: 2 new endovanilloids?

We recently investigated the possibility that 3-hydroxy-eicosatetraenoic acid (3-HETE), a fungal metabolite of AA produced by Candida albicans and related fungi via a fatty acid β-oxidation-related pathway (van Dyk et al., 1991), is capable to activate human recombinant TRPV1 receptors and, hence, to act as an endovanilloid. We found that in HEK293 cells overexpressing the human TRPV1, but not in wild-type HEK293 cells, 3-HETE dose-dependently elevated the intracellular Ca2+ concentration, this

Physiological and pathological processes potentially involving the endovanilloids as suggested by studies in which transient receptor potential vanilloid type 1 function is impaired

An idea of the potential physiological and pathological roles of endovanilloids can be gained also from studies in which TRPV1 receptors are impaired either genetically, as in TRPV1−/− mice, or by means of RNA interference techniques or following treatment with selective antagonists. In agreement with the proposed role of TRPV1 in the processing of multiple pain producing stimuli (Tominaga et al., 1998, Tominaga and Julius, 2000), it was first noted that TRPV1−/− mice exhibit an impaired

Concluding remarks

From the published evidence described in this article, it is possible to conclude that endovanilloids and TRPV1 receptors play important physiological and, particularly, pathological roles not only in the peripheral sensory nervous system but also in the brain and in non-nervous tissues. This conclusion opens the way to the development of synthetic compounds targeting either TRPV1 receptors or the enzymes responsible for endovanilloid biosynthesis and degradation as potential new therapeutic

Acknowledgments

KS and VDM are grateful to the Volkswagenstiftung for supporting their work on TRPV1 receptors in the brain, and to Dr. Luigia Cristino, Institute of Cybernetics, CNR, for preparing Fig. 3.

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