Catecholamines in human keratinocyte differentiation.

Abstract

Human keratinocytes have the capacity to synthesize catecholamines from L-tyrosine, which in turn is produced from L-phenylalanine via phenylalanine hydroxylase. This enzyme activity is controlled by the supply of the essential cofactor/electron donor (6R)5,6,7,8 tetrahydrobiopterin (6-BH4). Undifferentiated keratinocytes express high levels of the rate-limiting enzymes for the de novo synthesis of 6-BH4, i.e., GTP-cyclohydrolase-1, and for its recycling, i.e., 4a-hydroxytetrahydrobiopterin dehydratase. As a consequence of 6-BH4 synthesis, phenylalanine hydroxylase is activated, yielding L-tyrosine, which in the presence of excess 6-BH4 turns on the biosynthesis of catecholamines via the rate-limiting enzyme tyrosine hydroxylase. Therefore, undifferentiated keratinocytes contain high levels of the catecholamine system yielding sufficient levels of norepinephrine and epinephrine, required for the induction of beta-2-adrenoceptors. Stimulation of beta-2-adrenoceptors by epinephrine causes a rise in intracellular calcium via extracellular influx. This event corresponds with keratinocyte differentiation. In differentiated keratinocytes, all enzyme activities involved in 6-BH4, L-tyrosine, and epinephrine biosynthesis are decreased, resulting in significantly lower levels of epinephrine and a concomitant decrease in the expression of beta-2-adrenoceptors. These data strongly suggest a connection between catecholamine biosynthesis, beta-2-adrenoceptor expression, calcium flux, and the differentiation of keratinocytes in human epidermis.