The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1)

Abstract

Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.

Figure 1. Schematic diagram of a TRPV1 subunit in a lipid bilayer

The subunit has six transmembrane domains (red) and a pore loop between S5 and S6. The functional TRPV1 receptor is believed to form a tetramer. ‘A’ indicates ankyrin repeats shown as hexagons in the N terminus. Two calmodulin-binding regions in the N and C termini are indicated by CaM. The TRP box represents the TRP domain. Potentiators of TRPV1 are shown as green triangles, activators are shown as yellow rhombi, inhibitors are shown as black triangles and the residues interacting with these regulators are marked throughout the diagram.

Figure 2. Effects of LPA on TRPV1 function

For comparison, chemical structures of LPA 18:1 (A) and PIP₂ (B) are shown. C, currents elicited by a voltage protocol ranging from −120 mV to 120 mv with 10 mV steps and 100 ms duration in rat TRPV1 or human TRPV1-transfected HEK293 cells in the absence (left) and presence of 5 μm LPA (right). Application of LPA for 5 min elicits macroscopic TRPV1 currents. See Fig. 1 for binding sites of LPA and PIP₂.

Figure 3. Chemical structures of capsaicin and selected TRPV1 activators and positive regulators of TRPV1

Physiological concentrations for some activators and regulators of TRPV1 are shown in parentheses (Psychogios et al. 2011) and their EC₅₀ values for TRPV1 regulation are also shown.

Figure 4. Chemical structures of selective inhibitors and modulators of TRPV1

Physiological concentrations for some of these molecules are shown in parentheses (Psychogios et al. 2011) and the EC₅₀ values for TRPV1 regulation are also shown.

Figure 5. Docking-generated model for cholesterol binding to S5 in TRPV1

The model shows that cholesterol occupies a groove formed between S5 and the putative voltage-sensing domain of the adjacent subunit. Cholesterol's bulky β-face (shown in blue) points away from the S5 helix; the OH group (red and white) points toward Arg579, possibly establishing an electrostatic interaction. The α-face of cholesterol makes a hydrophobic π-aliphatic interaction with Phe582. The aliphatic tail in cholesterol occupies a small cavity where it interacts with L585 of TRPV1.