Aquaporin-3 in keratinocytes and skin: Its role and interaction with phospholipase D2

► Data support a key role for aquaporin-3 (a glycerol channel) in epidermal function. ► Lack of aquaporin-3 causes impaired keratinocyte proliferation and differentiation. ► Aquaporin-3 null mice exhibit delayed epidermal barrier recovery and wound healing. ► Transgenic mice overexpressing aquaporin-3 show accelerated barrier recovery. ► Elevated extracellular Ca 2+ levels increase keratinocyte aquaporin-3 glycosylation. Aquaporin 3 (AQP3) is an aquaglyceroporin that transports water and glycerol and is expressed in the epidermis, among other epithelial tissues. We have recently shown that there is an association between this glycerol channel and phospholipase D2 (PLD2) in caveolin-rich membrane microdomains. While PLD2 is able to hydrolyze membrane phospholipids to generate phosphatidic acid, this enzyme also catalyzes, in the presence of primary alcohols, a transphosphatidylation reaction to produce a phosphatidylalcohol. We have proposed that AQP3 associated with PLD2 provides the physiological primary alcohol glycerol to PLD2 for use in the transphosphatidylation reaction to generate phosphatidylglycerol (PG). Further, we have proposed that PG functions as a signaling molecule to mediate early epidermal keratinocyte differentiation, and manipulation of this signaling module inhibits keratinocyte proliferation and enhances differentiation. In contrast, other investigators have suggested a proliferative role for AQP3 in keratinocytes. In addition, AQP3 knockout mice exhibit an epidermal phenotype, characterized by dry skin, decreased elasticity and delayed barrier repair and wound healing, which can be corrected by glycerol but not other humectants. AQP3 levels have also been found to be altered in human skin diseases. In this article the evidence supporting a role for AQP3 in the epidermis will be discussed.