Epidermal Adrenergic Signal Transduction as Part of the Neuronal Network in the Human Epidermis

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NEUROGENIC CONTROL OF CUTANEOUS FUNCTION

Epidermal Adrenergic Signal Transduction as Part of the Neuronal Network in the Human Epidermis Karin U. Schallreuter Clinical and Experimental ])ermatology. Department of Biomedical Sciences. University of Bradford, Bradford, West Yorkshire, U.K.

Human keratinocytes have the full capacity for the

systetn has been followed in two distinct skin disor­

biosynthesis and degradation of catecholatnines. En­

ders: (i) vitiligo, and (ii) atopic eczetna. In vitiligo,

zymes in this biosynthetic pathway, as well as those

there is an overproduction of 6-BH4 leading to a

involved in the synthesis of the essential co-factor

dysregulation of catecholatnine biosynthesis with in­

(6R)L-erythro-S,6, 7,8-tetrahydrobiopterin

(6-BH4)

creased plastna and epidertnal norepinephrine levels

are expressed in keratinocytes producing the itnpor­

associated with high nutnbers of /32-adrenoceptors in

tant

epinephrine,

differentiating keratinocytes and with a defective

which control a high /32-adrenoceptor density on

hortnones

norepinephrine

and

calciutn uptake in both keratinocytes and tnelano­

undifferentiated/proliferating keratinocytes and the

cytes. In atopic eczetna, a point tnutation in the

expression of al-adrenoceptors on tnelanocytes. Re­

/32-adrenoceptor gene could alter the structure and

ceptor nutnbers correlate with calciutn

uptake or

function of the receptor, thereby leading to a low

release into the cell cytosol, which influences the

density of receptors on both keratinocytes and pe­

process of differentiation. After the differentiation

ripheral blood lytnphocytes. This review sutntnarizes

process, the enzytne activities, co-factors, and /32-

adrenoceptor

adrenoceptor densities decrease significantly in kera­

healthy epidertnis cotnpared to lesional epidertnis of

tinocytes, suggesting a tnajor function of this signal

patients with vitiligo or atopic eczetna. Key words:

transduction systetn in regulation of calciutn ho­

catecholamines/adrenoceptors/calcium. Journal of Investiga­ tive Dermatology Symposium Proceedings 2:37-40, 1997

meostasis in the epidertnis. The itnportance of this

I

structure

and

function

in

nortnal

n order to study the adrenergic response in the human

PNMT has been identitled (Schallreuter el ai, 1992). Activities for

epidermis, several factors must be considered: (i) the bio­

tyrosine hydroxylase and PNMT in epidermal extracts were com­

synthesis and degradation of the catecholamines from the

parable to those previously reported ill neuronal tissue (Lewinsohn

essential amino acid L-phenylalanine; (ii) the expression of

el ai, 1980). Only undifferentiated keratinocytes, however, ex­

adrenoceptors on keratinocytes and melanocytes it! llilJO and

pressed tyrosine hydroxylase and

PNMT

at

signitIcant levels

ill l'ilro; (iii) the structure and function of adrenoceptors in the

whereas the catecholamine biosynthetic pathway was absent in

epidermis; (iv) the relationship between the adrenergic response

both melanocytes and fibroblasts (Schallreuter et ai, 1992, 1995).

and other neuronal systems such as the cholinergic signal transduc­

The presence of TH,

tion pathways; and (v) the consequences of dysfunctional adrener­

cholamine-degrading enzyme, catechol-o-methyl-transferase, were

gic systems in the pathophysiology of various skin disorders.

contlrmed by immunohistochemical staining of the epidermis with Schallreuter el ai, 1995, 1996a). Very recently, Hyland (1996)1 has

THE EPIDERMIS ct

and the other cate­

monoclonal antibodies to these proteins (LePoole e/ ai, 1994;

CATECHOLAMINE SYNTHESIS AND DEGRADATION IN

In 1980, Lewinsohn

PNMT, MAO-A,

demonstrated that both epidermal and hair undife f rentiated kerati­

at found that human full-thickness skin

nocytes contain mRNAs for TH, two distinct forms for dopa

contained the c atecholarnine-degrading enzyme monoamine oxi­

decarboxylase and PNMT. The result on dopa decarboxylase is

dase A (MAO-A) (Lewinsohn

very interesting because this enzyme catalyzes both the decarbox­

('I

ai, 1980). A decade later, Elayan

('{

al (1990) measured the conversion of norepinephrine to epineph­

ylation

rine in rat skin catalyzed by phenylethanolamine-N-methyl trans­

tryptamine, suggesting that serotonin biosynthesis probably also

ferase (PNMT) (Elayan

occurs in human keratinocytes. The pathway for catecholamine

('I

ai, 1990). Upon examination of human

epidermal extracts, as well as extracts fi'om human keratinocytes,

of

L-dopa

to

dopamine

and

L-tryptophan

to

5-0H

synthesis is presented in Fig 1.

melanocytes, and tlbroblasts, the key enzyme for catecholamine

It has been well established that the synthesis of L-tyrosine from

biosynthesis, i.e., tyrosine hydroxylase as well as the presence of

L-phenylalanine and the control of L-dopa formation from L­ tyrosine depends on the rate-limiting co-factor/electron donor (6R)L-erythro-5,6,7,8-tetrahydrobiopterin (6-BH4) (Rembold and

Reprint requests to: Profesmr K.U. Schallreuter, Clinical and Experimen­ tal Dermatology, Department of Biomedical Sciences, University of Brad­ 1

ford, Bradford BD7 IDP, West Yorkshire, U.K.

Hyland K: Abnormalities of biogenic amine metabolism: clinical diag­

nostic and molecular aspects. Alois Niederwieser Memorial Lecture. 9th

Abbreviations: MAO-A, monoamine oxidase A; PNMT, phenylctha­ nolallline-N-methyl transferase; 6-BH", (6R)L-erythro-S,6,7,8-tetrahydro­

1I1tcmatiollai COllfer{'/1CC 011 Pteridincs. Port Douglas, Australia, May 19-24,

hiopterin.

1996, (abstr) Pteridil1cs (1996) in press.

1 OH7-01l24/97 IS1 O.SO

•

Copyright

1997 by The Society for Investigative Dermatology, Inc.

37

38

]IIJ SYMPOSIUM PROCEEDINGS

SCHALLREUTER

I

BIOSYNTHESIS OF CATECHOLAMINES

I 0,

L-PHENYLALANINE 6-BH,

HYDROXYLASE

L-TYROSINE 6-BH,

L

PHENYLALANINE

t

L-PHENYLALANINE

L-TYROSINE

=�=�::;:::------I .

TYROSINE

•

HYDROXYLASE

L-DOPA PYRIDOXAL-

L-AROMATIC AMINO ACID

•

PHOSPHATE

DECARBOXYLASE

DOPAMINE DOP AMINE-�-

t

ASCORBATE

HYDROXYLASE

NOREPINEPHRINE

GTP

S-ADENOSYL

PHENYLETHANOLAMINE-N-

•

METHIONINE

METHYLTRANSFERASE

Figure 2_ The itnportance of L-phenylalanine and 6-BH. for the synthesis of the catecholatnines in keratinocytes and tnelanins by

EPINEPHRINE

tnelanocytes. l30th epidermal melanocytes and keratinocytcs have the full

Figure 1_ Pathway for the biosynthesis of the catecholatnines frotn L-tyrosine_ Phenylalanine hydroxylase and tyrosine hydroxylase both use 6-BH4 as a co-factor leading to the synthesis of L-dopa, which is converted by the decarboxylase in the presence of pyridoxalphosphatc to dopamine. This metabolite is used by dopamine hydroxylase in the presence of ascorbate to form norepinephrine. Phenylethanolamine-N-methyl-trans­ ferase catalyzes the reaction to epinephrine in the presence of S-adenosyl­ illethionine.

capacity for

de

de

"''''0 synthesis/recycling of 6-BH4• The key enzyme for the

"ovo synthesis of 6-BH4

is GTP-cyclohydrolase I. This enzyme is

controlled by L-phenylalanine (positive feedback) as well as several cyto­ kines (tumor necrosis factor-a, mast cell growth factor, interleukin-2, and interferon-y). 6-BH4 is the essential co-factor (a) for phenylalanine hydrox­ ylase to metabolize L-phenylalanine to L-tyrosille, (b) for tyrosine hydrox­ ylase to convert L-tyrosine into L-dopa in the catecholamine biosynthesis in keratinocytes, and (c) a regulator of tyrosinase activity in melanocytes, where 6-BH4 inhibits the enzyme and the oxidized product 6-biopterin releases the activity. The recycling of6-BH4 is catalyzed by the rate-limiting 4a-hydroxy-BH4

dehydratase

via

quinonoid

dihydropterin

(qBH1).

If

6-l3H4 is overproduced, as in vitiligo, then 4a-OH l3H4 is nonenzymatically

Gyure, 1972). This important co-factor is synthesized by undiffer­

converted to micromolar levels of7-BH4 inhibiting phenylalanine hydrox­

entiated keratinocytes and melanocytes. It was shown that 6-BH4

ylase and consequently resulting in decreased L-tyrosine supply.

can control catecholamine biosynthesis in keratinocytes and mela­ nogenesis in melanocytes (Schallreuter

aI, 1994a, 1994b; Wood

et

ai, 1995). All of the enzyme activities and mRNAs for the de

flOPO

binding to membrane-associated {32-adrenoceptors. The {32-adre­

synthesis and recycling of 6-BH4 are present in both cel1s. The

noceptor is a 64-kDa protein that spans the plasma membrane with

et

central position

of 6-BH.

is presented in Fig 2,

rate-limiting enzyme for the de

flOPO

where the

synthesis of 6-BH4 is GTP

cyclohydrolase 1. The activity of this enzyme is controlled by the

seven trans-membrane-helices acting via a GTP-binding protein (G-protein). The G-proteins consist of

{3, and y subunits that

a,

remain associated due to GDP binding. If a signal activator such as

concentration of L-phenylalanine in the epidermis and by its own

norepinephrine or epinephrine binds to the receptor, the a subunit

ai, 1993). Furthermore,

dissociates to activate adenyl cyclase, yielding cAMP with a con­

metabolic end product 6-BH4 (Harada

et

GTP-cyclohydrolase I is induced by several cytokines (i.e., tumor necrosis factor-a

>

mast cel1 growth factor

interferon-y) (Ziegler, 1990; Werner

et

>

interleukin-2 >

ai, 1992). Consequently,

comitant uptake of calcium to increase the cytosolic concentration of this fast exchange ion (Kobilka

et

ai, 1987). One consequence of

this cascade of events is keratinocyte differentiation (Schallreuter

et

this enzyme plays a central role in the regulation of both catechol­

aI, 1995). After differentiation, the synthesis of the catecholamines

amine signal transduction and melanogenesis (Schallreuter, 1994a,

and the density of {32-adrenoceptors are significantly reduced. For

1994b).

melanocytes, the time-dependent induction of a1-adrenoceptors has been shown to depend on the extracellular concentration of

THE EXPRESSION OF ADRENOCEPTORS IN THE

norepinephrine (Schallreuter

HUMAN EPIDERMIS Gazith (1983) and later Steinkraus

et

al (1992) and Schal1reuter

et

ai, 1996b). This signal transduction

system activates the diacylglycerol/protein kinase C cascade with et

al

inosine triphosphate (IP 3 ) causing an increase in intracellular cal­

(1993) showed that human keratinocytes and split thickness skin

cium in the cytosol from intracellular stores present in the endo­

contain a high density of {32-adrenoceptors with 7,000 receptors/

plasmic reticulum. Differentiation of melanocytes ensues followed

cell. Recently, Schallreuter

et

al (1996) found that a1-adrenocep­

by the onset of melanogenesis

(Park

et

ai, 1993). Therefore,

tors (i.e., 4,000/cell) can be induced on melanocytes by extracel­

catecholamines produced by

undifferentiated

lular norepinephrine. The autocrine production of catecholamines

control

differentiation,

melanocyte

growth,

(Schallreuter function

true symbiotic relationship between these two cell types in the

suggested by Koizumi

epidermal unit. Koizumi

et

al (1992) were the first to show that

extracellular catecholamines can regulate calcium homeostasis via the {32-adrenoceptor signal in undife f rentiated keratinocytes, and

of the

systems in

the

epidermis,

as first

al (1993).

al (1995) found that undifferentiated human keratino­

Grando

cytes have the

MELANOCYTES

et

CHOLINERGIC SYSTEMS IN THE EPIDERMIS

in the control of intracellular calcium levels. THE STRUCTURE AND FUNCTION OF

adrenergic

THE RELATIONSHIP BETWEEN THE ADRENERGIC AND

they suggested a major function for adrenoceptors in the epidermis

ADRENOCEPTORS ON KERATINOCYTES AND

can

pigmentation

ai, 1996a). Clearly, calcium homeostasis is a central

by keratinocytes can control the expression of {32-adrenoceptors on keratinocytes and a1-adrenoceptors on melanocytes, suggesting a

et

keratinocytes and

et

capacity for the

synthesis

and degradation of

acetylcholine and express muscarinic receptors. On the other hand, differentiated keratinocytes primarily express nicotinic receptors (Grando

et

ai, 1996). The muscarinic receptors favor calcium efflux

from undifferentiated keratinocytes to promote both cell growth

The action of catecholamines in the epidermis on undifferentiated

and migration; meanwhile, the nicotinic receptors increase uptake

keratinocytes involves the modulation of cAMP and calcium by

of calcium to ensure dife f rentiation, maintaining the calcium gra-

VOL. 2,

NO.

I

AUGUST 1997

CATECHOLAMINES AND ADRENERGIC SIGNALS

dient in the epidermis (Menon et ai, 1985). As in neuronal tissue, it appears that adrenergic and cholinergic receptors act synergistically in the epidermis for the maintenance of calcium homeostasis (Grando et aI, 1995, 1996; Grando, 1997).

SKIN DISORDERS VITILIGO AND ATOPIC ECZEMA In the depigmentation disorder vitiligo, there is an

overproduction of 6-BH4 in both lesional and nonIesionaI epider­ mis (Schallreuter et aI,

39

CLOSING COMMENTS At the present time, our understanding of the adrenergic systems in the human epidermis is focused on two important control points: (i) the availability of the essential amino acid L-phenylalanine, and (ii)

EXAMPLES OF ADRENERGIC DYSFUNCTION IN THE

Vitiligo

IN SKIN

1994a, 1994b). The increased de

1101'0

synthesis of 6-BH4 is caused by a significant activation of GTP­ cy clohydrolase 1. In addition, 6-BH'1 cannot be efficiently recycled by 4a-hydroxy-6-BH4-dehydratase and consequently, the nonen­ zymatic isomer 7-BH4 accumulates in the epidermis in micromolar concentrations. These concentrations of 7-BH4 can inhibit phenyl­ alanine hydroxylase, thus preventing the synthesis of L-tyrosine from L-phenylalanine. 7-BH4 can also inhibit tyrosinase directly by an uncompetitive mechanism to stop melanogenesis in melanocytes (Wood ct aI, 1995). Excess 6-BH4 is oxidized to 6-biopterin, which accumulates in lesional skin, and it has been shown that it is cytotoxic to melanocytes under ill I'itro conditions (Schallrcuter ef

the de

1101'0

synthesis and recycling of 6-BH4• These two factors

appear to control the supply of L-tyrosine for melanogenesis in melanocytes and catecholamine synthesis/homeostasis in keratino­ cytes. Furthermore, this system is one important component in the control of the calcium gradient vis a vis differentiation and the cell cycle. The presence of the adrenergic signal transduction system, however, forms only one part of the neuronal network in the epidermis. The recent discovery of the cholinergic pathways by Grando et al (1995, 1996) suggests that cross-interactions must occur between the adrenergic and cholinergic signal transduction pathways as observed in other tissues. This important synergism in the human epidermis could play a major part in the establishment of the described calcium gradient from basal keratinocytes to the stratum granulosum. Unfortunately, at the present time, a complete understanding of tills scenario is still lacking, but certainly these systems must play an important role in various skin disorders.

ai, 1995). On the other hand, it was demonstrated that micromolar concentrations of 6-BH4 upregulate tyrosine hydroxylase by an allosteric mechanism (Naoi et aI, 1993). The high levels of 6-BH4 in

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40

JID SYMPOSIUM PROCEEDINGS

SCHALLREUTER

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