TRPV4: A Physio and Pathophysiologically Significant Ion Channel

Abstract

Transient Receptor Potential (TRP) channels are a family of ion channels whose members are distributed among all kinds of animals, from invertebrates to vertebrates. The importance of these molecules is exemplified by the variety of physiological roles they play. Perhaps, the most extensively studied member of this family is the TRPV1 ion channel; nonetheless, the activity of TRPV4 has been associated to several physio and pathophysiological processes, and its dysfunction can lead to severe consequences. Several lines of evidence derived from animal models and even clinical trials in humans highlight TRPV4 as a therapeutic target and as a protein that will receive even more attention in the near future, as will be reviewed here.

Keywords: TRP channels; TRPV4; disease; structure.

Figure 1

Structure of the TRPV4 channel. (A) Frontal view (top) and extracellular view (bottom) where one single subunit of the tetramer and each of its domains are shown in a different color (ARD in orange, β1 and β2 in blue, Helix Turn Helix in green, PreS1 in pink, S1–S4 in purple, S5–S6 in red, TRP box in magenta, and β3 in cyan). The membrane boundary is delimited by the black lines. (B) TRPV4 pore diameter. The structures of S6 and the pore helix of two subunits are shown. The distance between the two M714 residues is represented by the black line. (C) Top view of S1–S4 and S6 domains. Subunit domains follow the same color scheme as in A. The 6BBJ PDB file was used to produce this figure [70].

Figure 2

Function of TRPV4 in the vasculature. (A) Representation of a region of human vasculature and a cross section of an arteriole. (B) Activation of TRPV4 by different stimuli (i.e., 4α-phorbol 12,13-didecanoate or 4αPDD) leads to changes in intracellular Ca²⁺ levels, promoting the activity of the enzyme nitric oxide synthase (eNOS) and then increasing the levels of nitric oxide (NO). NO can cross endothelial cell membranes and activate other signaling pathways in smooth muscle cells, inducing vasodilation. Created with Biorender.com.

Figure 3

TRPV4 and lung damage. Stimuli such as the exposure to chemicals or mechanical stress (induced by liquids or a ventilator), lead to failure in the function of the alveolo-capillary (endothelial and epithelial cells) barrier with a consequent increase in their permeability, allowing for build-up of liquids in the alveoli. In addition to this, activation of TRPV4 in the alveolar macrophages results in an increase in intracellular Ca²⁺ and in the production of superoxide and nitric oxide (NO). Recently, the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) was identified and shown to cause the COVID-19 (coronavirus disease 19) that affects epithelial cells (type I and II) of the alveoli, promoting edema. TRPV4 could be involved in the inflammatory response caused by the SARS-CoV-2 virus. Since TRPV4 overactivation or overexpression can lead to damage in the alveolo-capillary barrier, it has been proposed that inhibitors of TRPV4 could result in a better outcome for COVID-19 patients [147], alveolar epithelial type I and II (ATI and ATII), 4α-phorbol 12,13-didecanoate (4αPDD) and 5, 6-epoxyeicosatrienoic acid (5, 6-EET). ROS, reactive oxygen species. Created with Biorender.com.

Figure 4

The activity of TRPV4 influences cyst growth and proliferation. (A) shows a normal kidney and nephron (top panel). The middle and lower panels show that when TRPV4 is adequately-expressed or activates normally, cell proliferation is kept under control. On the contrary, (B) shows that a polycystic kidney is full of fluid-filled structures which is a result of the lack of expression of correct function of TRPV4 (middle panel), resulting in abnormal proliferation and cyst formation (lower panel). Created with Biorender.com.

Figure 5

Location of mutations in different regions of the TRPV4 structure that produce skeletal dysplasia and neuromuscular disorders. (A) The top panel represents a subunit of the TRPV4 channel. I/Du = Insertion/Duplication. (B) The bottom panel summarizes the data in the top panel and the type of disease they produce as well as the effect of the mutation in channel function. PACSIN 3, protein kinase C and casein kinase substrate in neurons protein 3; ARD, ankyrin repeat domain; OS-9, osteosarcoma 9; TRP box, Transient Receptor Potential box; MAP7, microtubule associated protein 7; CaM, calcium calmodulin.

Figure 6

Three itch pathways associated to the function of TRPV4. When there are existing conditions such as dry skin, contact dermatitis, rosacea, etc., activation of TRPV4 in keratinocytes and in macrophages (that activate platelets) leads to the release of serotonin (5-HT) from these cells. 5-HT binds to its receptors in the itch fibers and this signal is transduced as itch in the central nervous system. Something similar occurs when TRPV4 channels in mast cells are overactivated or overexpressed, leading to the release of histamine that also activates receptors in itch fibers. It has also been proposed that UVB light damage, leads to the production of endothelin-1 that causes sunburn pain but could also cause post solar-burn itch through a mechanism not yet understood. 5-HTR, serotonin receptor. Created with Biorender.com.