Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis

Human keratinocytes have the full capacity for the biosynthesis and degradation of catecholamines. Enzymes in this biosynthetic pathway, as well as those involved in the synthesis of the essential co-factor (6R)L-erythro-5,6,7,8-tetrahydrobiopterin (6-BH4) are expressed in keratinocytes producing the important hormones norepinephrine and epinephrine, which control a high beta 2-adrenoceptor density on undifferentiated/proliferating keratinocytes and the expression of alpha 1-adrenoceptors on melanocytes. Receptor numbers correlate with calcium uptake or release into the cell cytosol, which influences the process of differentiation. After the differentiation process, the enzyme activities, co-factors, and beta 2-adrenoceptor densities decrease significantly in keratinocytes, suggesting a major function of this signal transduction system in regulation of calcium homeostasis in the epidermis. The importance of this system has been followed in two distinct skin disorders: (i) vitiligo, and (ii) atopic eczema. In vitiligo, there is an overproduction of 6-BH4 leading to a dysregulation of catecholamine biosynthesis with increased plasma and epidermal norepinephrine levels associated with high numbers of beta 2-adrenoceptors in differentiating keratinocytes and with a defective calcium uptake in both keratinocytes and melanocytes. In atopic eczema, a point mutation in the beta 2-adrenoceptor gene could alter the structure and function of the receptor, thereby leading to a low density of receptors on both keratinocytes and peripheral blood lymphocytes. This review summarizes adrenoceptor structure and function in normal healthy epidermis compared to lesional epidermis of patients with vitiligo or atopic eczema.