TRPV4

TRP channels are phylogenetically early signaling pathways (they can already be detected in yeast cells). The first TRP channel was identified in 1989 in connection with visual perception in Drosophila melanogaster. In a Drosophila mutant (trp343), it was shown that its photoreceptors responded to light stimuli only with a transient, i.e. rapidly inactivating, membrane current. In the non-mutated wild type, however, the current flow persisted as long as light hit the photoreceptor. The mutant protein -TRP- was cloned in 1989. Thus, the name "transient receptor potential" - TRP- refers to the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster.

The term "TRP channels" = transient receptor potential channels, summarizes a large family of cellular ion channels. In both vertebrates and non-vertebrates, TRP channels exert important functions in primary signaling pathways for the regulated influx of Ca2+ into a cell. TRP channels play important roles in humans in the sensation of different types of taste (sweet, bitter, umami) as well as in the perception of pain, heat, warmth or cold, pressure and light.

TRP channelopathies result from mutations in genes encoding TRP channels. This term covers several inherited human diseases affecting the cardiovascular, renal, skeletal, and nervous systems (Kaneko Y et al. 2014; Nilius B et al. 2011). TRP channels are also promising targets for drug development. For example, a number of potent small molecule TRPV1 channel antagonists (occasionally TRPM8 antagonists) are now showing therapeutic benefit in the treatment of inflammatory and neuropathic pain. (Moran MM et al. 2018)

TRPV4 is the 2nd heat channel next to TRP V3. TRP V4 has about 50% sequence identity to TRP V1. A hypotonic medium leads to activation of the channel.

Conversely, it is inhibited by increasing osmolarity. A sudden change in temperature can also activate the channel independent of osmolarity. A sustained temperature of > 43° results in a decreasing amplitude of the current even with increasing temperature. In contrast to TRP V3, TRP V4 does not show an increased current response after repeated heat stimuli.

Transient receptor potential channel subfamily V member 4 (TRPV4) is a polymodal, nonselective, calcium-permeable cation channel that is activated by both endogenous and exogenous stimuli. Both neuronal and non-neuronal cells express functional TRPV4 that responds to a variety of biochemical and biomechanical stimuli (Dutta B et al. (2019). Recent evidence suggests that TRPV4 plays an important role in a variety of pathological changes, such as fibrotic remodeling processes of the organism (myocardial fibrosis, cystic fibrosis, pulmonary fibrosis, liver fibrosis, and pancreatic fibrosis). Apparently, TRPV4 acts as a regulator of fibrosis progression (Zhan L et al. 2017). These findings could be a potential for new therapeutic approaches. Further studies demonstrate that TRP V4 plays an important role in the development of pulmonary hypertension (PH). Furthermore, in acute respiratory distress syndrome ARDS (Scheraga RG et al. 2020).

In pulmonary hypertension, TRPV4 activation in adventitia fibroblasts (PAF) leads to increased expression of extracellular matrix protein synthesis(collagen type I and fibronectin - Cussac LA et al. 2019). Recent findings have expanded our understanding of the role of TRPV4 in macrophage activity in numerous inflammatory diseases. For example, in phagocytosis, foreign body reactions (Dutta B et al. 2019).

Animal experiments have shown that deletion of TRPV4 in macrophages suppresses allergic and non-allergic itch (Dutta B et al. 2019).

In TRPV4 knockout mice, TRPV4 antagonism exhibits therapeutic potential in edema and pain. Furthermore, also in inflammatory gastrointestinal and pulmonary diseases (Grace MS et al. 2017).

Of note, TRP V3 and TRPV4 are expressed in skin cells. While keratinocytes contribute to hyperalgesia through the release of inflammatory mediators following injury, their direct role in thermosensation is unclear.

1. Cussac LA et al (2019) TRPV4 channel mediates adventitial fibroblast activation and adventitial remodeling in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 318:L135-L146.
2. Dutta B et al (2019) Role of macrophage TRPV4 in inflammation. Lab Invest 100:178-185.
3. Grace MS et al (2017) Modulation of the TRPV4 ion channel as a therapeutic target for disease. Pharmacol Ther 177:9-22.
4. Michalick L et al (2020) TRPV4-A Missing Link Between Mechanosensation and Immunity. Front Immunol 11:413.
5. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
6. Scheraga RG et al (2020) The Role of TRPV4 in Regulating Innate Immune Cell Function in Lung Inflammation. Front Immunol 11:1211.
7. Shibasaki K (2016) TRPV4 ion channel as important cell sensors. J Anesth 30:1014-1019.
8. Vogt-Eisele AK et al (2007) Monoterpenoid agonists of TRPV3. Br J Pharmacol 151:530-540.
9. Wang Y et al. (2017) Targeting Transient Receptor Potential Canonical Channels for Diseases of the Nervous System. Curr Drug Targets.18:1460-1465.
10. Zhan L et al. (2017) The role of TRPV4 in fibrosis. Gene 642:1-8.