报告表明,TRPV4和anocamin1(ANO1)之间的相互作用可能广泛参与外分泌腺的水流出,表明这种相互作用可能在出汗中起作用。在小鼠脚垫中存在的汗腺分泌细胞中,TRPV4明显与细胞角蛋白8、ANO1和水通道蛋白-5(AQP5)共定位。小鼠汗腺显示TRPV4依赖性细胞溶质Ca2增加,被薄荷醇抑制。在野生型中,乙酰胆碱刺激的脚垫出汗是温度依赖性的,但在TRPV4缺陷型小鼠中没有,并且在野生型和TRPM8KO小鼠中均受到薄荷醇的抑制。无乙酰胆碱刺激的基础出汗被ANO1抑制剂抑制。出汗对于保持鼠标脚垫的摩擦力可能很重要,这种可能性得到了以下发现的支持:野生型小鼠比TRPV4缺陷型小鼠更容易爬上滑坡。此外,与AIGA患者的无汗症皮肤相比,获得性特发性全身性无汗症(AIGA)患者的对照组和无汗症皮肤中的TRPV4表达明显更高。总的来说,TRPV4可能通过与ANO1的相互作用参与温度依赖性排汗,TRPV4本身或TRPV4/ANO1复合物将靶向开发调节排汗的药物。
应力,辛辣的食物和升高的温度都可以触发专门的腺细胞将水移动到皮肤上-换句话说,他们可以让我们出汗。这个过程是我们的身体调节温度和避免中暑等危及生命的疾病的最重要方法之一。这种功能受损的疾病,如AIGA(获得性特发性全身性无汗症),构成重大健康风险。寻找汗液相关疾病的治疗方法需要详细了解出汗背后的分子机制,这还没有实现。最近的研究强调了两种离子通道的作用,TRPV4和ANO1,在调节产生眼泪和唾液的腺体中的液体分泌。这些门样蛋白控制着某些离子进出细胞的方式,这也会影响水的运动。一旦被外部刺激激活,TRPV4允许钙离子进入细胞,导致ANO1打开和氯离子离开。这导致水也通过专用通道离开细胞,在被收集在连接到身体外部的管道中之前。TRPV4,通过加热激活,也存在于人类汗腺细胞中。这促使Kashio等人。为了检查这些通道在汗液产生中的作用,专注于小鼠以及AIGA患者。使用荧光抗体探测TRPV4,ANO1和AQP5(一种水通道)水平证实,这些通道都存在于小鼠脚垫的相同汗腺细胞中。进一步的实验强调TRPV4通过ANO1活化介导这些动物的汗液产生。由于啮齿动物不能通过出汗来调节体温,Kashio等人。探索了脚掌出汗的生物学益处。缺乏TRPV4的小鼠出汗减少,爬上湿滑的斜坡的能力下降,表明一层汗水有助于改善牵引力。最后,Kashio等人。比较了健康志愿者和AIGA患者的样本,发现受该疾病影响的个体的TRPV4水平较低。总的来说,这些发现揭示了对出汗的潜在机制的新见解,TRPV4是AIGA等疾病的潜在治疗靶点。结果还表明,可以通过诸如TRPV4之类的热传感通道检测到的温度的局部变化来控制出汗。这将偏离我们目前的理解,即出汗完全由自主神经系统控制,它调节非自愿的身体功能,如唾液和泪液的产生。
Reports indicate that an interaction between TRPV4 and anoctamin 1 (ANO1) could be widely involved in water efflux of exocrine glands, suggesting that the interaction could play a role in perspiration. In secretory cells of sweat glands present in mouse foot pads, TRPV4 clearly colocalized with cytokeratin 8, ANO1, and aquaporin-5 (AQP5). Mouse sweat glands showed TRPV4-dependent cytosolic Ca2+ increases that were inhibited by menthol. Acetylcholine-stimulated sweating in foot pads was temperature-dependent in wild-type, but not in TRPV4-deficient mice and was inhibited by menthol both in wild-type and TRPM8KO mice. The basal sweating without acetylcholine stimulation was inhibited by an ANO1 inhibitor. Sweating could be important for maintaining friction forces in mouse foot pads, and this possibility is supported by the finding that wild-type mice climbed up a slippery slope more easily than TRPV4-deficient mice. Furthermore, TRPV4 expression was significantly higher in controls and normohidrotic skin from patients with acquired idiopathic generalized anhidrosis (AIGA) compared to anhidrotic skin from patients with AIGA. Collectively, TRPV4 is likely involved in temperature-dependent perspiration via interactions with ANO1, and TRPV4 itself or the TRPV4/ANO 1 complex would be targeted to develop agents that regulate perspiration.
Stress, spicy foods and elevated temperatures can all trigger specialized gland cells to move water to the skin – in other words, they can make us sweat. This process is one of the most important ways by which our bodies regulate their temperature and avoid life-threatening conditions such as heatstroke. Disorders in which this function is impaired, such as AIGA (acquired idiopathic generalized anhidrosis), pose significant health risks. Finding treatments for sweat-related diseases requires a detailed understanding of the molecular mechanisms behind sweating, which has yet to be achieved. Recent research has highlighted the role of two ion channels, TRPV4 and ANO1, in regulating fluid secretion in glands that produce tears and saliva. These gate-like proteins control how certain ions move in or out of cells, which also influences water movement. Once activated by external stimuli, TRPV4 allows calcium ions to enter the cell, causing ANO1 to open and chloride ions to leave. This results in water also exiting the cell through dedicated channels, before being collected in ducts connected to the outside of the body. TRPV4, which is activated by heat, is also present in human sweat gland cells. This prompted Kashio et al. to examine the role of these channels in sweat production, focusing on mice as well as AIGA patients. Probing TRPV4, ANO1 and AQP5 (a type of water channel) levels using fluorescent antibodies confirmed that these channels are all found in the same sweat gland cells in the foot pads of mice. Further experiments highlighted that TRPV4 mediates sweat production in these animals via ANO1 activation. As rodents do not regulate their body temperature by sweating, Kashio et al. explored the biological benefits of having sweaty paws. Mice lacking TRPV4 had reduced sweating and were less able to climb a slippery slope, suggesting that a layer of sweat helps improve traction. Finally, Kashio et al. compared samples obtained from healthy volunteers with those from AIGA patients and found that TRPV4 levels are lower in individuals affected by the disease. Overall, these findings reveal new insights into the underlying mechanisms of sweating, with TRPV4 a potential therapeutic target for conditions like AIGA. The results also suggest that sweating could be controlled by local changes in temperature detected by heat-sensing channels such as TRPV4. This would depart from our current understanding that sweating is solely controlled by the autonomic nervous system, which regulates involuntary bodily functions such as saliva and tear production.