ATP-sensitive potassium channel: a novel target for protection against UV-induced human skin cell damage.
Ultraviolet radiation (UV) induces cell damages leading to skin photoaging and skin cancer. ATP-sensitive potassium (K(ATP)) channel openers (KCOs) have been shown to exert significant myocardial preservation and neuroprotection in vitro and in vivo, and yet the potential role of those KCOs in protection against UV-induced skin cell damage is unknown. We investigated the effects of pinacidil and diazoxide, two classical KCOs, on UV-induced cell death using cultured human keratinocytes (HaCat cells). Here, we demonstrated for the first time that Kir 6.1, Kir 6.2 and SUR2 subunits of K(ATP) channels are functionally expressed in HaCaT cells and both non-selective K(ATP) channel opener pinacidil and mitoK(ATP) (mitochondrial K(ATP)) channel opener diazoxide attenuated UV-induced keratinocytes cell death. The protective effects were abolished by both non-selective K(ATP) channel blocker glibenclamide and selective mitoK(ATP) channel blocker 5-hydroxydecanoate (5-HD). Also, activation of K(ATP) channel with pinacidil or diazoxide resulted in suppressive effects on UV-induced MAPK activation and reactive oxygen species (ROS) production. Unexpectedly, we found that the level of intracellular ROS was slightly elevated in HaCaT cells when treated with pinacidil or diazoxide alone. Furthermore, UV-induced mitochondrial membrane potential loss, cytochrome c release and ultimately apoptotic cell death were also inhibited by preconditioning with pinacidil and diazoxide, and their effects were reversed by glibenclamide and 5-HD. Taken together, we contend that mitoK(ATP) is likely to contribute the protection against UV-induced keratinocytes cell damage. Our findings suggest that K(ATP) openers such as pinacidil and diazoxide may be utilized to prevent from UV-induced skin aging.
Cao
Cong
C
Department of Biology, Providence College, Providence, Rhode Island 02918, USA.
Healey
Sarah
S
Amaral
Ashley
A
Lee-Couture
Avery
A
Wan
Shu
S
Kouttab
Nicola
N
Chu
Wenming
W
Wan
Yinsheng
Y
D000255:Adenosine Triphosphate / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020110:Pinacidil / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D020110:Pinacidil; D000255:Adenosine Triphosphate; D003981:Diazoxide