Catecholamines in human keratinocyte differentiation.
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.
Schallreuter
K U
KU
Department of Dermatology, University of Hamburg, Germany.
Lemke
K R
KR
Pittelkow
M R
MR
Wood
J M
JM
Körner
C
C
Malik
R
R
D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D002454:Cell Differentiation; D004837:Epinephrine / Q000096:biosynthesis*; D006706:Homeostasis; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry; D015603:Keratinocytes / Q000166:cytology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D013997:Time Factors
D002132:Calcium Radioisotopes; D018343:Receptors, Adrenergic, beta-2; D001708:Biopterins; C003402:sapropterin; D002118:Calcium; D004837:Epinephrine