The Role of TRPV4 in Temperature-Dependent Perspiration in Mice

Core Concepts

TRPV4 and its interaction with the calcium-activated chloride channel ANO1 play a crucial role in temperature-dependent perspiration in mice, with implications for understanding and treating human sweating disorders.

Abstract

The study investigated the involvement of the temperature-sensitive ion channel TRPV4 in the regulation of perspiration in mice. The researchers found that TRPV4 is expressed and functionally active in mouse sweat gland secretory cells, where it colocalizes with the calcium-activated chloride channel ANO1 and the water channel AQP5.
Experiments showed that stimulated and basal sweating in mouse hind paws was temperature-dependent, with increased sweating at higher temperatures in wild-type mice but not in TRPV4-deficient mice. Menthol, which inhibits both TRPV4 and ANO1, reduced sweating in both wild-type and TRPM8-deficient mice, suggesting that the inhibition of TRPV4 and ANO1 contributes to the cooling sensation of menthol. Furthermore, the ANO1 inhibitor Ani9 almost completely abolished basal sweating, indicating a pivotal role of ANO1 in the sweating process.
The researchers also found that TRPV4 expression was significantly higher in normohidrotic skin from patients with acquired idiopathic generalized anhidrosis (AIGA) compared to anhidrotic skin from the same patients, suggesting that TRPV4 plays an important role in human perspiration as well. The TRPV4-ANO1 complex could be a target for developing agents to regulate perspiration and treat sweating disorders.

Stats

Acetylcholine-stimulated sweating in foot pads was temperature-dependent in wild-type, but not in TRPV4-deficient mice.
Basal sweating without acetylcholine stimulation was inhibited by an ANO1 inhibitor.
Wild-type mice climbed up a slippery slope more easily than TRPV4-deleted mice.
TRPV4 expression was significantly higher in normohidrotic skin from patients with AIGA compared to anhidrotic skin.

Quotes

"TRPV4 is likely involved in temperature-dependent perspiration via interactions with ANO1, and TRPV4 itself or the TRPV4/ANO 1 complex would be targets to develop agents that regulate perspiration."
"Problems with exocrine gland function in Sjögren's syndrome patients as well as the low TRPV4 expression levels in patients with AIGA suggest that TRPV4 could be a key molecule involved in these diseases and that novel treatment strategies could target TRPV4 and/or ANO1."

Key Insights Distilled From

Involvement of TRPV4 in temperature-dependent perspiration in mice

by Kashio,M., D... at www.biorxiv.org 10-29-2023

https://www.biorxiv.org/content/10.1101/2023.10.25.563940v2

Deeper Inquiries

How might the TRPV4-ANO1 complex be targeted therapeutically to regulate perspiration in sweating disorders?

The TRPV4-ANO1 complex could be targeted therapeutically in sweating disorders by developing agents that modulate the function of either TRPV4, ANO1, or the complex itself. Since the interaction between TRPV4 and ANO1 plays a crucial role in water efflux in exocrine glands, including sweat glands, targeting this complex could help regulate perspiration. One approach could involve developing specific inhibitors or activators of TRPV4 or ANO1 to modulate their function. For example, menthol, which inhibits both TRPV4 and ANO1, could be used to reduce sweating. Additionally, targeting the TRPV4/ANO1 complex directly could provide a more specific and effective way to regulate perspiration in conditions of hypo- or hyperhidrosis.

What other physiological processes beyond perspiration could be influenced by the interaction between TRPV4 and ANO1?

The interaction between TRPV4 and ANO1 could influence various physiological processes beyond perspiration due to the widespread expression of these channels in different tissues and cell types. One potential process that could be influenced is saliva and tear secretion, as both processes involve the secretion of fluids by exocrine glands. The TRPV4-ANO1 complex could play a role in regulating the secretion of saliva and tears by modulating water efflux in the salivary and lacrimal glands. Additionally, the interaction between TRPV4 and ANO1 could impact nociception in primary sensory neurons, as Ca2+ entering cells through TRPV4 activates ANO1, leading to Cl- efflux and potentially affecting pain perception.

What are the potential implications of the temperature-dependent regulation of sweating by TRPV4 for understanding thermoregulation and adaptation in different environmental conditions?

The temperature-dependent regulation of sweating by TRPV4 has significant implications for understanding thermoregulation and adaptation in different environmental conditions. TRPV4's involvement in temperature-dependent sweating suggests that sweat glands themselves can sense local heating and initiate sweating through TRPV4 activation. This local temperature sensation could provide a rapid and localized response to changes in environmental temperature, contributing to overall thermoregulation. Understanding the role of TRPV4 in temperature-dependent sweating could shed light on how the body adapts to different environmental conditions, such as heat exposure or cold stress, by modulating sweat production to maintain optimal body temperature. Additionally, targeting TRPV4 in conditions where thermoregulation is compromised, such as in patients with hypohidrosis or hyperhidrosis, could lead to novel therapeutic strategies for managing temperature dysregulation.