Human skin epidermal adenylate cyclase systems: defective beta-adrenergic responsiveness in the involved epidermis of Darier's disease.

It has been reported that pig skin epidermis contains at least four independent adenylate cyclase systems, i.e. 1) beta-adrenergic-, 2) histamine H2-, 3) adenosine and, 4) prostaglandin E-adenylate cyclase systems, resulting in the accumulation of cyclic AMP. Using human skin epidermis, we investigated the responses of adenylate cyclase to epinephrine, histamine, and adenosine. In normal human skin, all three agents increased cyclic AMP levels of the skin. The epinephrine effect was inhibited by a beta-adrenergic blocking agent, propranolol. The histamine effect was inhibited by a histamine H2 inhibitor, cimetidine. The adenosine effect was inhibited by theophylline. The effects of epinephrine and histamine were augmented by the addition of the cyclic AMP phosphodiesterase inhibitor, theophylline. Another phosphodiesterase inhibitor, papaverine, augmented the effects of all three agents. In contrast to pig skin epidermis, where histamine and adenosine-induced cyclic AMP accumulations were marked, in human skin, epinephrine-induced cyclic AMP accumulation was more marked than those induced by histamine and adenosine. Using the epidermis of Darier's disease, we also investigated the effects of epinephrine, histamine and adenosine on the cyclic AMP levels of the skin. The involved skin of Darier's disease was shown to be characterized by a defective beta-adrenergic responsiveness. These findings show that normal human skin possesses at least three independent adenylate cyclase systems (beta-adrenergic, histamine H2-, and adenosine-adenylate cyclase), as in pig skin epidermis, with a different responsiveness pattern to these stimulators. Our data also show that the responsiveness to each receptor-adenylate cyclase system may be modified in a pathological condition of epidermis such as in Darier's disease. The significance of decreased beta-adrenergic responsiveness in the involved skin in Darier's disease was discussed in relation to our previous finding of the same type of defect in the psoriatic-involved epidermis.