TRPV1: Structure, Endogenous Agonists, and Mechanisms

Abstract

The Transient Receptor Potential Vanilloid 1 (TRPV1) channel is a polymodal protein with functions widely linked to the generation of pain. Several agonists of exogenous and endogenous nature have been described for this ion channel. Nonetheless, detailed mechanisms and description of binding sites have been resolved only for a few endogenous agonists. This review focuses on summarizing discoveries made in this particular field of study and highlighting the fact that studying the molecular details of activation of the channel by different agonists can shed light on biophysical traits that had not been previously demonstrated.

Keywords: TRP channels; TRPV1; agonist; pain; structure.

Figure 1

Structure of TRPV1 depicted with different agonists bound to various sites in the protein. Except for (A) capsaicin (that binds to residues Y512, S513, T551, and E571), all other agonists are endogenously produced: (B) 20-hydroxyeicosatetraenoic acid (20-HETE, which interacts with residue S502); (C) anandamide (which interacts with residues Y511, S512, and R591); (D) oxytocin (which interacts with residues E600, G602, Y631, and L635); and (E) lysophosphatidic acid (LPA, which binds to the K710 residue). The 3j5q PDB file that corresponds to the open structure (obtained with RTX and DkTx) of TRPV1 [41] was used. The black squares represent the regions of the channel where the different depicted endogenous agonists bind.

Figure 2

Products of linoleic acid (LA) that activate TRPV1. LA is the precursor of several long-chain polyunsaturated fatty acids including arachidonic acid, 9-HODE, and 13-HODE. All byproducts downstream of the lipooxygenase and cytochrome P450 (CYP450) pathway shown in this scheme have been proposed to activate TRPV1 [51,52].

Figure 3

α-linolenic acid (ALA, n-3) activates TRPV1. ALA is a precursor of EPA and EPA is transformed into 20-HEPE via ω-oxidation and into DHA through elongation reactions. 22-HDoHE is a polyunsaturated fatty acid which is derived from DHA through a ω-hydroxylation reaction catalyzed by the cytochrome P450 enzyme omega-hydroxylase.

Figure 4

N-acyl amides with agonist effects on TRPV1. The family of N-acyl GABA molecules that are structurally related is shown in the top panel. The middle and lower panels depict the structures of other N-acyl amides that arise from different families and that do not necessarily share functional groups but also activate TRPV1.