Molecular and Physiological Functions of PACAP in Sweat Secretion

Sweat has a critical role in human body, including thermoregulation and maintenance of skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion resulting in severe skin conditions (pruritus and erythema). Bioactive peptide, pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and identified to activate adenylate cyclase in pituitary cells. In recent years, it was reported that PACAP increases sweat secretion via PAC1R in mice and promotes the translocation of AQP5 to the cell membrane through increasing intercellular [Ca2+] via PAC1R in NCL-SG3 cells. However, the intracellular signaling mechanisms by PACAP are poorly clarified. In this study, we used PAC1R knockout (KO) mice and wild-type (WT) mice to observe changes in AQP5 localization and gene expression in sweat gland by PACAP treatment. Immunohistochemistry revealed that PACAP promotes the translocation of AQP5 to lumen side in eccrine gland via PAC1R. Furthermore, PACAP up-regulates gene expression (Ptgs2, Kcnn2, Cacna1s) involved in sweat secretion in WT mice. Further, PACAP treatment down-regulated Chrna1 gene expression in PAC1R KO mice. These genes were found to be involved in multiple pathways related to sweating. Overall our data provide a solid basis for future research initiatives to develop new therapies to treat sweating disorders. After intradermal injection of PACAP to six WT mice and PAC1R KO mice each, the skin of the paws was sampled at 30 and 60 minutes later, which were immersed immediately post-dissection in liquid nitrogen and thereafter transferred to an -80°C deep freezer. The samples were individually ground in liquid nitrogen to prepare very fine powders for subsequent downstream gene expression analyses. The Agilent mouse whole genome 4 × 44 K (G4122F) DNA slide (composed of 4 chips on one slide) was used for the microarray analysis, which was performed according to manufacturer’s instructions.