Study examines role of the gene TRPV4 in regulating perspiration in mice

Sweating is a vital process in a normally functioning body. Generally sweating occurs to regulate body temperature or as a response to stimuli such as stress. Most sweat glands are of the eccrine type. These eccrine sweat glands are distributed all over the body, but their density is greatest in the armpit and on the palms of the hands and the soles of the feet. In humans, eccrine sweat glands’ main function is to regulate body temperature. The apocrine sweat glands that become active during puberty are found mainly in the armpit and genital areas of the body.

Wanting to better understand these processes at work in perspiration, the team conducted their research examining the sweat glands in the foot pads of mice. In their study, they worked with wild-type (or “normal”) mice and TRPV4-deficient mice for comparison. Their observations revealed that TRPV4, anoctamin 1 (calcium-activated chloride-channel protein) and aquaporin-5 (a water-channel protein) seem to form a complex that promotes sweat secretion in the eccrine gland of the mouse foot pads.

Mice do not sweat to control their body temperature, so scientists are unsure of the physiological significance of sweating on their hind paws. In humans, fingertip moisture is controlled during object manipulation through the regulation of friction force. Scientists wonder if the same mechanism might provide traction on the hind paws of mice when they climb the slippery slope. So the team constructed a slippery slope experiment and compared the climbing behaviors of mice.  The evidence showed that TRPV4-deficient mice didn’t climb the slippery slope well compared with normal mice, suggesting that sweating could be important for maintaining friction forces in mouse food pads.

Their next step was to examine whether TRPV4 also played a role in human perspiration. Their research included a study of the skin of patients with Acquired Idiopathic Generalized Anhidrosis or AIGA, a rare disorder that is characterized by the absence of sweating, even when the person is exposed to heat or is engaged in exercise. Their data clearly indicated that TRPV4 plays a role in normal perspiration in humans.

Scientists know that there is an interaction between the TRPV4 protein and the anoctamin 1 protein that impacts water leaving the exocrine glands. This suggests that the interaction plays a role in perspiration. “The involvement of TRPV4 in exocrine gland function prompted us to examine the functional interaction in perspiration, because TRPV4 is expressed in human eccrine sweat glands,” said Makoto Tominaga, a professor at the National Institutes of Natural Sciences in Japan. The team determined that the functional interaction of TRPV4 and anoctamin 1 is involved in temperature-dependent sweating and increased friction force. Tominaga said “Perspiration could be regulated by local temperature sensing through TRPV4 in addition to the activities in autonomic nervous system”

There are several human diseases that involve hypohidrosis (the absence of sweating) or hyperhidrosis (excessive sweating). Patients with hypohidrosis struggle to regulate their body temperature in response to high temperatures and can experience dizziness, muscle cramps, weakness, high fever or nausea that is typically not serious. However, heatstroke, a much more serious complication, can occur in patients with hypohidrosis. Heatstroke is occurring much more frequently with the increase in global warming. Hypohidrosis can also be a problem for patients with collagen diseases like Sjögren’s syndrome, a chronic autoimmune disease that is not easily treated.

Hyperhidrosis can occur in patients as a primary or secondary symptom after infections or in connection with some endocrine diseases. Others can experience hyperhidrosis on the palms of their hands related to nervousness. “The development of chemicals targeting TRPV4, ANO1 or the complex could be a new therapeutic strategy for these conditions, for which there are currently no effective treatments,” said Tominaga.

The research team includes Makiko Kashio, Sandra Derouiche, Jing Lei, Makoto Tominaga from the National Institutes of Natural Sciences; Reiko U. Yoshimoto and Mizuho A. Kido from Saga University; and Kenji Sano from Iida Municipal Hospital. Kashio also works at Kumamoto University. Tominaga also works at Nagoya City University.