TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function

Abstract

The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1's actions in the homeostasis of Ca²⁺ in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.

Keywords: ROS; TRPV1; apoptosis; mitochondrial dysfunction; nociception; pain.

Figure 1

The Transient Receptor Potential (TRP) superfamily of ion channels. TRP ion channels are classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA1 (ankyrin) and TRPN (no mechanoreceptor). The figure shows the phylogenetic analysis between the human TRP protein sequences; the alignment was obtained using ClustalW2 at the EMBL-EBI server. For TRPC2 (pseudogene) and TRPN (not expressed in humans), the sequences used were from mice and fish, respectively. The channels colored in dark-, light-blue and red refer to some of the channels known as the thermo-TRP, since there are activated by cool, cold and hot temperatures (TRPM81, TRPA1 and TRPV1, respectively). The figure also shows the tetrameric 3D-structure of a representative member of each subfamily. TRPM8 (6O6A), TRPC3 (6CUD), TRPN (5VKQ), TRPA1 (3J9P), TRPV1 (3J5P) TRPP2 (5K47) and TRPML1 (5WJ5). The symbols beneath each 3D-structure are the number access in the Protein Data Bank (PDB).

Figure 2

Structural features of the TRPV1 protein. (a) This figure schematizes the domains of a TRPV1 monomer (or subunit). The amino- and carboxy- termini are intracellularly located (N- and C- termini), the six ankyrin repeats and the TRP-box are contained in the N- and C-termini, respectively. The re-entrant loop between the S5–S6 forms the ionic conduction pore when the tetramer is formed. (b) 3D-representation of a TRPV1 subunit displaying the arrangement of the domains represented in (a). S1–S6: transmembrane segments.

Figure 3

Scheme representing plasmatic TRPV1 actions on mitochondria. (a) Prolonged activation of TRPV1 leads to Ca²⁺ overload into the mitochondria. This effect triggers mitochondrial depolarization, releases cytochrome C through the permeability transition pore (PTP) and induces apoptosis. (b) Activation of TRPV1 induces the mitochondrial fission and produces axonal degeneration. (c) Downregulation of the Na⁺/Ca²⁺/Li²⁺ exchanger (NCLX) expression avoids the release of Ca²⁺ from the mitochondria, which inhibits mitochondrial Ca²⁺ uptake through the mitochondrial Ca²⁺ uniporter (MCU), leading to accumulation of cytosolic Ca²⁺ and inducing TRPV1 desensitization. ER: endoplasmic reticulum. AEA: N-arachidonoylethanolamine or Anandamide. NADA: N-Arachidonoyl-Dopamine.