Hydrogen peroxide-mediated oxidative stress disrupts calcium binding on calmodulin: more evidence for oxidative stress in vitiligo.
Patients with acute vitiligo have low epidermal catalase expression/activities and accumulate 10(-3) M H(2)O(2). One consequence of this severe oxidative stress is an altered calcium homeostasis in epidermal keratinocytes and melanocytes. Here, we show decreased epidermal calmodulin expression in acute vitiligo. Since 10(-3)M H(2)O(2) oxidises methionine and tryptophan residues in proteins, we examined calcium binding to calmodulin in the presence and absence of H(2)O(2) utilising (45)calcium. The results showed that all four calcium atoms exchanged per molecule of calmodulin. Since oxidised calmodulin looses its ability to activate calcium ATPase, enzyme activities were followed in full skin biopsies from lesional skin of patients with acute vitiligo (n=6) and healthy controls (n=6). The results yielded a 4-fold decrease of ATPase activities in the patients. Computer simulation of native and oxidised calmodulin confirmed the loss of all four calcium ions from their specific EF-hand domains. Taken together H(2)O(2)-mediated oxidation affects calcium binding in calmodulin leading to perturbed calcium homeostasis and perturbed l-phenylalanine-uptake in the epidermis of acute vitiligo.
Schallreuter
K U
KU
Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, Bradford BD7 1DP, UK. k.schallreuter@bradford.ac.uk
Gibbons
N C J
NC
Zothner
C
C
Abou Elloof
M M
MM
Wood
J M
JM
D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage*; D008956:Models, Chemical; D008958:Models, Molecular; D018384:Oxidative Stress / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D014820:Vitiligo / Q000378:metabolism*
D002147:Calmodulin; D006861:Hydrogen Peroxide; D002118:Calcium