The Epidermis and Cyclic Amp

A hormone induces a rapid and profound change in the metabolic balance of its target organ. Early studies emphasized the extraordinarily low concentrations in which many hormones are effective. The fact that catechoiamines and polypeptides are frequently unable to penetrate the surface of cells made this seem all the more remarkable. The mechanism of their action, which for many years remained a central problem of molecular biology, was finally resolved by the discovery of adenosine 3',5'monophosphate (cyclic AMP) in 1958 by Sutherland & Rail. It subsequently became apparent that cyclic AMP was the intracellular second messenger for those hormones that by themselves could not penetrate inside the cell. An overall but abbreviated sequence of events is shown in Fig. i. When activated by cyclic AMP, a cyclic AMP dependent protein kinase may phosphorylate many different proteins, both enzymatic and structural. In some cases this results in their activation, whereas in others the protein is converted to a biologically inactive form. Thus, co-ordinate control over several different pathways is accomplished. In addition, the amplification obtained by linking enzymic reactions in cascade is considerable; one may visualize how a cell could respond to a very few molecules of the external hormone (the 'first messenger'). The most comprehensive review of the general literature is the monograph of Robison, Butcher & Sutherland (1971), which includes a bibliography of over 1500 references to cyclic AMP. It is notable but not surprising that this literature deals with almost every mammalian tissue except epidermis. Does the 'second messenger' system in fact operate in mammalian epidermis ? Adenylate cyclase activity was first described in homogenates of whole guinea-pig skin (Mier & Urselmann, 1970a), but no hormonal stimulation could be demonstrated. Using a particulate fraction isolated from epidermis, Duell et ah (1971) and Marks & Rebien (1972a) were able to show some degree of stimulation by catechoiamines, although this was still very small compared with other tissues. Intact epidermal cells, on the other hand, respond vigorously; for example, Powell, Duell & Voorhees (1971) found a threefold increase in the cyclic AMP content of rat epidermis following exposure to isoproterenol, and Bronstad, Elgjo and 0ye (1971) reported increases of more than ten-fold in the synthesis of cyclic AMP by whole hamster skin in response to adrenalin. Thus, it is now clear that this part, at least, of the system is functional The other two enzymes shown in Fig. r have now also been described in mammalian skin. The enzyme responsible for lowering cellular levels of cyclic AMP after hormonal stimulation has ceased, cyclic AMP phosphodiesterase, was examined in whole mouse skin (Mier & Urselmann, 1972) and found to have a Kn, of 9 x I O ' ^ M and was inhibited by methyl xanthines. The high K ,̂ cyclic AMP phosphodiesterase has been measured in both involved and uninvolved psoriasis epithelium and appears to be unaltered (Voorhees et al.y 1973a). The low K ,̂ aaivity might be increased in the lesion in comparison to the uninvolved areas (Voorhees et ah, 1974a). Cychc AMP dependent protein kinase has been investigated in whole human skin (Kumar, Tao & Solomon, 1971), in whole mouse skin (Mier & van den Hurk, 1972) and in human epidermis (Voorhees et al., 1974b); the cutaneous enzyme seems very similar to those from other tissues. Although certain of these results pertain to whole skin, the preponderance of epidermal cells in such preparations and the demonstration of all the components of the cyclic AMP system in human epidermis (Voorhees et ah, 1974a) makes it