Beyond Neuronal Heat Sensing: Diversity of TRPV1 Heat-Capsaicin Receptor-Channel Functions

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable ion channel best known for its ability to be gated by the pungent constituent of red chili pepper, capsaicin, and related chemicals from the group of vanilloids as well as by noxious heat. As such, it is mostly expressed in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Its activation is also sensitized by the numerous endogenous inflammatory mediators and second messengers, making it an important determinant of nociceptive signaling. Except for such signaling, though, neuronal TRPV1 activation may influence various organ functions by promoting the release of bioactive neuropeptides from sensory fiber innervation organs. However, TRPV1 is also found outside the sensory nervous system in which its activation and function is not that straightforward. Thus, TRPV1 expression is detected in skeletal muscle; in some types of smooth muscle; in epithelial and immune cells; and in adipocytes, where it can be activated by the combination of dietary vanilloids, endovanilloids, and pro-inflammatory factors while the intracellular calcium signaling that this initiates can regulate processes as diverse as muscle constriction, cell differentiation, and carcinogenesis. The purpose of the present review is to provide a clear-cut distinction between neurogenic TRPV1 effects in various tissues consequent to its activation in sensory nerve endings and non-neurogenic TRPV1 effects due to its expression in cell types other than sensory neurons.

Keywords: TRPV1; adipocytes; epithelia cells; sensory neuron; smooth muscle.

FIGURE 1

Schematic depiction of TRPV1 channel membrane topology with major functional domains. TRPV1 channel is a tetramer composed of four TRPV1 subunits arranged around a central ion-conducting aqueous pore. Only one TRPV1 subunit is shown in color (not to scale) with the second one disposed at 180° to it depicted in gray; the third (at 90°) and fourth (at 270°) subunits are omitted to open the view. Cylinders – α-helical segments, including S1…S6 transmembrane domains, P pore(P)-loop α-helix, ARD1-6 – ankyrin-repeat domains, TRP box and S4–S5 linker. Parts of TRPV1 subunit contributing to ion-conducting pore are presented in burgundy-orange. Amino acids involved in PIP2 binding are presented according to Poblete et al. (2015).

FIGURE 2

Diagram of TRPV1 expression and function in various tissues. GPCR – G protein-coupled receptor, NTKR – neurotrophic tyrosine kinase receptor, ASM – arterial smooth muscle, SkM – skeletal muscle, BAT – brown adipose tissue, WAT – white adipose tissue, IBD – inflammatory bowel disease.

FIGURE 3

The modes of neurogenic (blue) and non-neurogenic (green and pink) TRPV1 involvement in regulation of arterial function through its expression in perivascular sensory nerves and vascular endothelial and smooth muscle cells. It is likely that the resultant effect of TRPV1 activation on vasculature and blood pressure in vivo would depend on a number of factors: the agonist’s nature and concentration, time of exposure (acute or chronic), route of administration (local, oral, intravenous), site of application, the presence of sensitizing or desensitizing agents that together would determine the prevalence of either constrictory or relaxant action. These factors may dynamically modulate TRPV1 activation and Ca²⁺ permeability through the phenomenon known as TRPV1 pore dilation (Chung et al., 2008) to shape TRPV1 participation in blood pressure regulation. CGRP – calcitonin gene related peptide, GPCR – G protein-coupled receptor, NTKR – neurotrophic tyrosine kinase receptor, SMC – smooth muscle cells, SP – substance P.