Kcnh2 and Kcnj8 interactively regulate skin wound healing and regeneration

Abstract

Previous studies indicate that ion channels are mediators of bioelectricity promoting wound closure/regeneration in nonmammalian, lower vertebrate systems. The role of ion channels however in regeneration of wounds in mammalian systems that do not regenerate as adults is not yet defined. Using a mammalian model system that allows us to determine differentially expressed genes when skin regenerates and when skin does not regenerate after wound induction, we identified two potassium channels, kcnh2 and kcnj8, to be (1) differentially expressed between the two states and (2) highly expressed after wound induction at the nonregenerative state. We also found that kcnh2 small molecule inhibitor enhanced wound healing while kcnj8 small molecule inhibitor did not. In contrast, kcnj8 activator accelerated wound healing and even augmented the effect of kcnh2 inhibition. These results provide evidence for the first time that potassium channels may mediate skin wound healing and regeneration interactively.

The Role of Early Bioelectric Signals in the Regeneration of Planarian Anterior/Posterior Polarity

“…Bioelectric physiology is an important component of repair and regeneration in numerous model systems (32,53,(74)(75)(76)(77)(78)(79)(80)(81). Endogenous bioelectric fields have been shown to regulate many patterning, morphological, and regenerative processes (32,(82)(83)(84)(85)(86) and to serve as instructional prepatterns (87,88).…”

4-aminopyridine promotes accelerated skin wound healing

“…These prior ndings make the effects of 4-AP somewhat surprising because it is thought that 4-AP treatment leads to increased calcium release as an indirect effect of potassium channel inhibition and by direct activation of high voltage-activated calcium channels 31,62 , and 4-AP is also used clinically to treat verapamil overdose 63 . It also has been observed that skin wound healing can be enhanced by inhibition of the KCNH2 potassium channel 33 , but this channel is not known to be a target of 4-AP. As previous studies did not examine the range of cell types and cellular modulators that we studied, it is not possible to determine if these other interventions were as effective as 4-AP.…”

“…In contrast with the effects of 4-AP in chronic syndromes, in which there is no evidence for alterations in tissue structure and where bene ts disappear in concurrence with clearance of 4-AP from the body 25,26 , effects in acute injuries include restoration of normal tissue structure and durable functional improvement 20,21,27−30 . However, it is plausible that 4-AP could actually worsen skin wound healing, as several studies have reported that calcium channel blockers enhance repair of such injuries [31][32][33] , and 4-AP is predicted to increase calcium release.…”

4-aminopyridine promotes accelerated skin wound healing via neurogenic-mediator expression

“…These prior findings make the effects of 4-AP somewhat surprising because it is thought that 4-AP treatment leads to increased calcium release as an indirect effect of potassium channel inhibition and by direct activation of high voltage-activated calcium channels 31,58 , and 4-AP also is used clinically to treat verapamil overdose 59 . It also has been observed that skin wound healing can be enhanced by inhibition of the kcnh2 potassium channel 33 , but this channel is not known to be a target of 4-AP. As previous studies did not examine the range of cell types and cellular modulators that we studied, it is not possible to determine if these other interventions were as effective as 4-AP.…”

“…In contrast with the effects of 4-AP in chronic syndromes, in which there is no evidence for alterations in tissue structure and where benefits disappear in concurrence with clearance of 4-AP from the body 25,26 , effects in acute injuries include restoration of normal tissue structure and durable functional improvement 20,21,[27][28][29][30] . However, it is plausible that 4-AP could actually worsen skin wound healing, as several studies have reported that calcium channel blockers enhance repair of such injuries [31][32][33] , and 4-AP is predicted to increase calcium release.…”