FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2209631778> ?p ?o ?g. }

• W2209631778 endingPage "353" @default.
• W2209631778 startingPage "346" @default.
• W2209631778 abstract "Earlier it has been shown that human proliferating/undifferentiated basal keratinocytes hold the full capacity for autocrine catecholamine synthesis/degradation and express β2-adrenoceptors (β2-AR). In this report, we show that human melanocytes also express all of the mRNA and enzymes for autocrine synthesis of norepinephrine but fail to produce epinephrine. So far, it was established that human melanocytes express α1-AR which are induced by norepinephrine yielding the inosine triphosphate diacylglycerol signal. The presence of catecholamine synthesis and the β2-AR signal escaped definition at that time. Using RT-PCR, immunofluorescence and radioligand binding with the β2-AR antagonist (-)-[3H]CGP 12177, we show here that human melanocytes express functional β2-AR (4230 receptors per cell) with a Bmax at 129.3 and a KD of 3.19 nM but lack β1-AR expression. β2-AR stimulation with epinephrine 10-6 M and salbutamol 10-6–10-5 M yielded a strong cyclic adenosine monophospate (cAMP) response in association with upregulated melanin production. Taken together these results indicate that the biosynthesis and release of epinephrine (10-6 M) by surrounding keratinocytes can provide the cAMP response leading to melanogenesis in melanocytes via the β2-AR signal. Moreover, the discovery of this catecholaminergic cAMP response in melanocytes adds a new source for this important second messenger in melanogenesis. Earlier it has been shown that human proliferating/undifferentiated basal keratinocytes hold the full capacity for autocrine catecholamine synthesis/degradation and express β2-adrenoceptors (β2-AR). In this report, we show that human melanocytes also express all of the mRNA and enzymes for autocrine synthesis of norepinephrine but fail to produce epinephrine. So far, it was established that human melanocytes express α1-AR which are induced by norepinephrine yielding the inosine triphosphate diacylglycerol signal. The presence of catecholamine synthesis and the β2-AR signal escaped definition at that time. Using RT-PCR, immunofluorescence and radioligand binding with the β2-AR antagonist (-)-[3H]CGP 12177, we show here that human melanocytes express functional β2-AR (4230 receptors per cell) with a Bmax at 129.3 and a KD of 3.19 nM but lack β1-AR expression. β2-AR stimulation with epinephrine 10-6 M and salbutamol 10-6–10-5 M yielded a strong cyclic adenosine monophospate (cAMP) response in association with upregulated melanin production. Taken together these results indicate that the biosynthesis and release of epinephrine (10-6 M) by surrounding keratinocytes can provide the cAMP response leading to melanogenesis in melanocytes via the β2-AR signal. Moreover, the discovery of this catecholaminergic cAMP response in melanocytes adds a new source for this important second messenger in melanogenesis. β2-adrenoceptor dopadecarboxylase dopamine-β-hydroxylase oligo deoxythymidine triphosphate; phenylethanolamine-N-methyltransferase pro-opiomelanocortins tyrosine hydroxylase Catecholamines are a group of signalling molecules, which serve two primary biological functions, acting as neurotransmitters and as endocrine hormones (Martini, 1999). Earlier, it has been shown that human proliferating/undifferentiated basal keratinocytes hold the full capacity for autocrine catecholamine biosynthesis and degradation via monoamine oxidase A (EC 1.4.3.4, MAO-A) and catechol-O-methyltransferase (EC 2.1.1.6, COMT) (Schallreuter et al., 1992Schallreuter K.U. Wood J.M. Lemke R. et al.Production of catecholamines in the human epidermis.Biochem Biophys Res Commun. 1992; 189: 72-78Crossref PubMed Scopus (102) Google Scholar,Le Poole et al., 1994Le Poole I.C. van den Wijngaard R.M. Smit N.P. Oosting J. Westerhof W. Pavel S. Catechol-O-methyltransferase in vitiligo.Arch Dermatol Res. 1994; 286: 81-86Crossref PubMed Scopus (38) Google Scholar;Schallreuter et al., 1996aSchallreuter K.U. Wood J.M. Pittelkow M.R. Büttner G. Swanson N. Körner C. Ehrke C. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo.Arch Dermatol Res. 1996; 288: 14-18Crossref PubMed Scopus (92) Google Scholar). The rate-limiting step for catecholamine biosynthesis is the conversion of L-tyrosine to L-dopa by tyrosine hydroxylase (EC 1.14.16.2, TH) (Nagatsu et al., 1964Nagatsu T. Levitt M. Udenfriend S. Conversion of L-tyrosine to 3,4-dihydroxyphenylalanine by cell-free preparations of brain and sympathetically innervated tissues.Biochem Biophys Res Commun. 1964; 14: 543-549Crossref PubMed Scopus (68) Google Scholar). TH-activity depends on the availability of its essential cofactor/electron donor 6R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (6BH4) to form L-dopa. In this context, it has been shown that de novo synthesis/recycling/regulation of 6BH4 occurs in both human epidermal keratinocytes and melanocytes (Schallreuter et al., 1994aSchallreuter K.U. Wood J.M. Pittelkow M.R. et al.Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin.Science. 1994; 263: 1444-1446Crossref PubMed Scopus (307) Google Scholar, Schallreuter et al., 1994bSchallreuter K.U. Wood J.M. Ziegler I. Lemke K.R. Pittelkow M.R. Lindsey N.J. Gütlich M. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo.Biochim Biophys Acta. 1994; 1226: 181-192Crossref PubMed Scopus (146) Google Scholar). L-dopa is converted to dopamine by dopadecarboxylase (EC 4.1.1.28, DDC) in the presence of pyridoxal phosphate. Subsequently, dopamine is oxidized to norepinephrine by dopamine-β-hydroxylase (EC 1.14.17.1, DβH). The last enzyme phenylethanolamine-N-methyltransferase (EC 2.1.1.28, PNMT) specifically catalyses the synthesis of epinephrine from norepinephrine in the presence of S-adenosyl-L-methionine (SAM) (for review seeSchallreuter et al., 1992Schallreuter K.U. Wood J.M. Lemke R. et al.Production of catecholamines in the human epidermis.Biochem Biophys Res Commun. 1992; 189: 72-78Crossref PubMed Scopus (102) Google Scholar) (Figure 1). Nowadays, it is well established that catecholamine signalling involves the activation of β2 adrenoceptors (β2-AR) on the cell plasma membrane (Schramm and Selinger, 1984Schramm M. Selinger Z. Message transmission: Receptor controlled adenylate cyclase system.Science. 1984; 225: 1350-1356Crossref PubMed Scopus (196) Google Scholar;Carafoli and Penniston, 1985Carafoli E. Penniston J.T. The calcium signal.Sci Am. 1985; 253: 70-78Crossref PubMed Scopus (111) Google Scholar;Gilman, 1987Gilman A.G. G proteins: Transducers of receptor-generated signals.Annu Rev Biochem. 1987; 56: 615-649Crossref PubMed Scopus (4711) Google Scholar). The β2-AR is a 64 kDa protein which belongs to the G-protein-coupled receptor (GPCR) family (Robison et al., 1967Robison G.A. Butcher R.W. Sutherland E.W. Adenyl cyclase as an adrenergic receptor.Ann N Y Acad Sci. 1967; 139: 703-723Crossref PubMed Scopus (433) Google Scholar). All GPCR share a common architecture with seven transmembrane helices, where an intracellular domain is involved in recognition and activation of G-proteins (Wess, 1997Wess J. G-protein-coupled receptors: Molecular mechanisms involved in receptor activation and selectivity of G-protein recognition.FASEB J. 1997; 11: 346-354Crossref PubMed Scopus (511) Google Scholar). The G-proteins, which are heterotrimers made up of distinct α, β and γ subunits, transduce ligand binding to the GPCR into an intracellular response. β-adrenergic receptors activate adenylylcyclase (AC), leading to an increase in intracellular cyclic adenosine monophospate (cAMP) concentrations followed by activation of protein kinase A (PKA) and an increase in intracellular calcium (Koizumi et al., 1991Koizumi H. Yasui C. Fukaya T. Ohkawara A. Ueda T. Beta-adrenergic stimulation induces intracellular Ca++ increase in human epidermal keratinocytes.J Invest Dermatol. 1991; 96: 234-237Abstract Full Text PDF PubMed Google Scholar;Steinkraus et al., 1992Steinkraus V. Steinfath M. Körner C. Mensing H. Binding of beta-adrenergic receptors in human skin.J Invest Dermatol. 1992; 98: 475-480Abstract Full Text PDF PubMed Scopus (62) Google Scholar;Yasui et al., 1992Yasui C. Koizumi H. Fukaya T. Kumakiri M. Ohkawara A. Ueda T. Adenylate cyclase induces intracellular calcium increase in single human epidermal keratinocytes measured by fluorescence microscopy using Fura 2-AM.Br J Dermatol. 1992; 127: 589-594Crossref PubMed Scopus (11) Google Scholar). Earlier, it has been recognized that proliferation and differentiation of human keratinocytes depend on calcium concentrations (Boyce and Ham, 1983Boyce S.T. Ham R.G. Calcium-regulated differentiation of normal human epidermal keratinocytes in chemically defined clonal culture and serum-free serial culture.J Invest Dermatol. 1983; 81: 33s-40sCrossref PubMed Scopus (958) Google Scholar;Grando, 1997Grando S.A. Biological function of keratinocyte cholinergic receptors.J Investig Dermatol Symp Proc. 1997; 2: 41-48Abstract Full Text PDF PubMed Scopus (221) Google Scholar). An epidermal calcium gradient with low calcium concentration in the basal layer and increasing calcium concentrations in the upper layers has been documented (Menon et al., 1985Menon G.K. Grayson S. Elias P.M. Ionic calcium reservoirs in mammalian epidermis: Ultrastructural localization by ion-capture cytochemistry.J Invest Dermatol. 1985; 84: 508-512Crossref PubMed Scopus (389) Google Scholar). Moreover, it has also been shown that β2-AR density in the human epidermis depends on the calcium concentration (Gazith and Reichert, 1982Gazith J. Reichert U. High affinity membrane receptors in cultured human keratinocytes. I. The beta-adrenergic receptors.Br J Dermatol. 1982; 107: 125-133Crossref PubMed Scopus (6) Google Scholar;Schallreuter et al., 1993Schallreuter K.U. Wood J.M. Pittelkow M.R. Swanson N.N. Steinkraus V. Increased in vitro expression of beta2-adrenoceptors in differentiating lesional keratinocytes of vitiligo patients.Arch Dermatol Res. 1993; 285: 216-220Crossref PubMed Scopus (52) Google Scholar), where undifferentiated keratinocytes express approximately 7500 AR per cell and differentiated keratinocytes express only 2500 receptors underlining an important function for the β2-AR in the differentiation process in human skin (Schallreuter et al., 1995Schallreuter K.U. Lemke K.R. Pittelkow M.R. Wood J.M. Körner C. Malik R. Catecholamines in human keratinocyte differentiation.J Invest Dermatol. 1995; 104: 953-957Crossref PubMed Scopus (109) Google Scholar). But catecholamine synthesis in melanocytes escaped recognition under the experimental conditions used at that time (Schallreuter et al., 1992Schallreuter K.U. Wood J.M. Lemke R. et al.Production of catecholamines in the human epidermis.Biochem Biophys Res Commun. 1992; 189: 72-78Crossref PubMed Scopus (102) Google Scholar). It was later reported that melanocytes express α1-AR yielding stimulation of the inosine triphosphate/diacylglycerol signal cascade (Schallreuter et al., 1996bSchallreuter K.U. Körner C. Pittelkow M.R. Swanson N.N. Gardner M.L. The induction of the alpha-1-adrenoceptor signal transduction system on human melanocytes.Exp Dermatol. 1996; 5: 20-23Crossref PubMed Scopus (28) Google Scholar). At that time, it was assumed that these receptors relied on norepinephrine synthesis by surrounding keratinocytes and not by autocrine stimulation (Schallreuter et al., 1996bSchallreuter K.U. Körner C. Pittelkow M.R. Swanson N.N. Gardner M.L. The induction of the alpha-1-adrenoceptor signal transduction system on human melanocytes.Exp Dermatol. 1996; 5: 20-23Crossref PubMed Scopus (28) Google Scholar). Only very recently the expression and enzymatic function of tyrosine hydroxylase isoform I (TH-1) was demonstrated in the cytosol of keratinocytes and melanocytes and in melanosomes (Marles et al., 2003Marles L.K. Peters E.M. Tobin D.J. Hibberts N.A. Schallreuter K.U. Tyrosine hydroxylase isoenzyme I is present in human melanosomes: A possible novel function in pigmentation.Exp Dermatol. 2003; 12: 61-70Crossref PubMed Scopus (52) Google Scholar). The presence of TH-1, side by side with tyrosinase on the melanosomal membrane in association with L-dopa formation underlined the importance of L-dopa for activation of tyrosinase in the control of pigmentation (Marles et al., 2003Marles L.K. Peters E.M. Tobin D.J. Hibberts N.A. Schallreuter K.U. Tyrosine hydroxylase isoenzyme I is present in human melanosomes: A possible novel function in pigmentation.Exp Dermatol. 2003; 12: 61-70Crossref PubMed Scopus (52) Google Scholar). Moreover, the presence of TH-1 in the cytosol of melanocytes leads us to readdress the question whether these cells express the other enzymes for complete biosynthesis of catecholamines (i.e., DDC, DβH, and PNMT) together with a functional β-AR signal. The results of this study identified the presence of an autocrine norepinephrine biosynthesis in melanocytes using RT-PCR and in vitro and in situ immunofluorescence. RT-PCR showed the presence of β2-AR mRNA but failed to detect β1-AR mRNA. Saturation binding studies yielded 4230 β2-AR/cell with low affinity (KD=3.19 nM). Consequently, we tested the function of the β2-AR in these cells under in vitro conditions by following cAMP production and melanogenesis upon stimulation with epinephrine or salbutamol. Our results demonstrate a functional β2-AR signal on human melanocytes unmasking an additional cAMP source in these cells in association with increased melanogenesis. Since it has been established that the α-melanocyte stimulating hormone (α-MSH)/cAMP cascade stimulates melanogenesis, our findings indicate that the β2-AR/cAMP response also contributes significantly to pigmentation (Abe et al., 1969aAbe K. Butcher R.W. Nicholson W.E. Baird C.E. Liddle R.A. Liddle G.W. Adenosine 3′, 5′-monophosphate (cyclic AMP) as the mediator of the actions of melanocyte stimulating hormone (MSH) and norepinephrine on the frog skin.Endocrinology. 1969; 84: 362-368Crossref PubMed Scopus (95) Google Scholar,Abe et al., 1969bAbe K. Robison G.A. Liddle G.W. Butcher R.W. Nicholson W.E. Baird C.E. Role of cyclic AMP in mediating the effects of MSH, norepinephrine, and melatonin on frog skin color.Endocrinology. 1969; 85: 674-682Crossref PubMed Scopus (120) Google Scholar;Pavel and Schwippelova, 1978Pavel S. Schwippelova Z. Importance of MSH and cyclic 3′,5′-adenosine monophosphate for regulation of melanogenesis (author's transl).Cesk Dermatol. 1978; 53: 57-61PubMed Google Scholar;Miyazaki et al., 1984Miyazaki K. Goldman M.E. Kebabian J.W. Forskolin stimulates adenylate cyclase activity, adenosine 3′, 5′-monophosphate production and peptide release from the intermediate lobe of the rat pituitary gland.Endocrinology. 1984; 114: 761-766Crossref PubMed Scopus (21) Google Scholar;Thody et al., 1984Thody A.J. Ridley K. Carter R.J. Lucas A.M. Shuster S. Alpha-MSH and coat color changes in the mouse.Peptides. 1984; 5: 1031-1036Crossref PubMed Scopus (21) Google Scholar;Abdel Malek et al., 1986aAbdel Malek Z.A. Hadley M.E. Bregman M.D. Meyskens Jr, F.L. Hruby V.J. Actions of melanotropins on mouse melanoma cell growth in vitro.J Natl Cancer Inst. 1986; 76: 857-863PubMed Google Scholar,Abdel Malek et al., 1986bAbdel Malek Z.A. Kreutzfeld K.L. Hadley M.E. Bregman M.D. Hruby V.J. Meyskens Jr, F.L. Long-term and residual melanotropin-stimulated tyrosinase activity in S91 melanoma cells is density dependent.In Vitro Cell Dev Biol. 1986; 22: 75-81Crossref PubMed Google Scholar;Rees and Flanagan, 1999Rees J.L. Flanagan N. Pigmentation, melanocortins and red hair.Q J Med. 1999; 92: 125-131Crossref Scopus (33) Google Scholar). hTH-1-specific RT-PCR assays clearly showed the expression of hTH-1 mRNA in undifferentiated keratinocytes (n=2) and epidermal melanocytes (n=2) (Figure 2a). Subsequent Pst 1 restriction analysis of the amplified product validated the assay (data not shown); however, mRNA expression for any other TH isoforms could not be detected in either human melanocytes or keratinocytes in vitro. Based on this result it was concluded that human epidermal melanocytes and keratinocytes do not express other isoforms of TH, except hTH-1. Figure 2b shows the expression of DDC mRNA in two different undifferentiated keratinocyte and two different melanocyte cell lines. Figure 2c shows the presence of mRNA for PNMT in two different undifferentiated keratinocyte and two different melanocyte cell lines. In summary, these results demonstrated the presence of transcription for complete catecholamine synthesis in melanocytes under in vitro conditions. To further substantiate the translation of the identified mRNA of catecholamine biosynthesis in human melanocytes, cell cultures were used for immunohistochemical detection. The results presented in Figure 3a show the presence of TH as “cytoplasmic granules” with peri-nuclear and dendritic tip accumulations. DDC staining identifies the presence of cellular subpopulations where immature cells stain profusely whereas the mature, multi-dendritic cells fail to stain (Figure 3b). The results for DβH are similar; however, only a small number of cells, approximately less than 10%, fail to stain (Figure 3c). In each case, the pattern of staining appears granular and is found in the majority of cells to be restricted to the cell periphery and to the dendrites. The peri-nuclear staining pattern, as demonstrated with TH, was not observed for either DDC or DβH. Figure 3d shows the absence of PNMT protein expression in melanocytes under the experimental conditions used in this study. In order to ensure the specificity of the antibody, we used undifferentiated keratinocytes of the same culture age (p4), as positive controls (Figure 3d, iii). This result shows that despite the presence of mRNA, translation of this last enzyme in the catecholamine synthesis is absent in melanocytes under the experimental conditions used. Figure 4 shows the expression of β2-AR mRNA on human epidermal melanocytes. To our knowledge these results demonstrate for the first time the transcription of the β2-AR in human epidermal melanocytes. To ensure the nature of the product obtained from the RT-PCR assays, sequence analysis was performed. The results confirmed that the amplicons were indeed the targeted gene regions and not spurious products of non-specific annealing (data not shown); however, we were unable to detect β1-AR mRNA in melanocytes under the experimental conditions used (data not shown). In order to further substantiate successful translation of mRNA expression for β2-AR on melanocytes, we performed immunofluorescence on full-skin sections and on cell cultures of melanocytes. β2-AR protein expression was pronounced in undifferentiated/basal keratinocytes (Figure 5a). This result is in agreement with higher levels of catecholamine biosynthesis and β2-AR expression in the proliferating cells of the basal layer as described earlier (Schallreuter et al., 1992Schallreuter K.U. Wood J.M. Lemke R. et al.Production of catecholamines in the human epidermis.Biochem Biophys Res Commun. 1992; 189: 72-78Crossref PubMed Scopus (102) Google Scholar). In addition, we identified melanocyte-specific β2-AR expression by double immunostaining, using the melanocyte-specific gp 100 protein (NKI/Beteb). β2-AR expression on melanocytes in situ was visualized upon overlaying of both fluorophores (Figure 5a, inset i). Furthermore, the presence of β2-AR protein expression was also demonstrated in melanocytes under in vitro conditions (Figure 5b). In order to determine the density of receptors in melanocytes, specific saturation binding assays were performed. The specific binding of (-)-[3H]CGP 12177 to human melanocytes is saturated as a function of radioligand concentration. Figure 6 presents the specific binding on human melanocytes. The number of receptors present on each cell were calculated as outlined in methods. Based on this calculation, each cell expressed 4230 receptors with a Bmax at 129.3 and a KD of 3.19 nM. This result is in agreement with low-affinity β2-AR on melanocytes; however, the receptor number on these cells differs significantly from the receptor density and affinity on undifferentiated keratinocytes, i.e., 7500 β2-AR/keratinocyte and a KD of 0.095 nM (Steinkraus et al., 1991Steinkraus V. Körner C. Steinfath M. Mensing H. High density of beta2-adrenoceptors in a human keratinocyte cell line with complete epidermal differentiation capacity (HaCaT).Arch Dermatol Res. 1991; 283: 328-332Crossref PubMed Scopus (18) Google Scholar;Schallreuter et al., 1993Schallreuter K.U. Wood J.M. Pittelkow M.R. Swanson N.N. Steinkraus V. Increased in vitro expression of beta2-adrenoceptors in differentiating lesional keratinocytes of vitiligo patients.Arch Dermatol Res. 1993; 285: 216-220Crossref PubMed Scopus (52) Google Scholar). To test the specificity and functionality of this receptor, we investigated the β2-AR by following cAMP production after epinephrine or salbutamol stimulation in different concentrations. The results demonstrated a concentration-dependent cAMP production upon stimulation with both epinephrine and salbutamol, confirming the low-affinity response as indicated by the KD (Figure 6). The most effective response was observed after 10-6 and 10-5 M epinephrine or salbutamol stimulation (Figure 6 and Figure 7). The concentration of epinephrine is in the physiological range in keratinocytes (Schallreuter et al., 1992Schallreuter K.U. Wood J.M. Lemke R. et al.Production of catecholamines in the human epidermis.Biochem Biophys Res Commun. 1992; 189: 72-78Crossref PubMed Scopus (102) Google Scholar). In order to test the specific β2-AR/cAMP response on melanogenesis, cells were incubated for 48 h with salbutamol. Figure 7b demonstrates a concentration-dependent increase in melanin content after exposure to this β2-AR specific agonist.Figure 7Increased cyclic adenosine monophospate (cAMP) and melanin production in human melanocytes after stimulation with salbutamol. The result shows cAMP production in human melanocytes after simulation with a specific β2-adrenoceptor agonist salbutamol (10-8–10-5 M) compared with unstimulated controls. The inset shows melanin production after stimulation with the same ligand for 48 h. The melanin formation follows cAMP response at the same concentrations. All experiments were performed in duplicates. The results are in agreement with low-affinity receptor response as observed after stimulation with epinephrine.View Large Image Figure ViewerDownload (PPT) To our knowledge, the results presented herein are original and demonstrate the presence of norepinephrine biosynthesis in human melanocytes in association with a functioning β2-adrenergic signal leading to both increased cAMP production and melanogenesis. Interestingly, these cells do not express β1-AR. Only recently, the importance of TH isoform I was documented in the initiation of melanogenesis in melanosomes (Marles et al., 2003Marles L.K. Peters E.M. Tobin D.J. Hibberts N.A. Schallreuter K.U. Tyrosine hydroxylase isoenzyme I is present in human melanosomes: A possible novel function in pigmentation.Exp Dermatol. 2003; 12: 61-70Crossref PubMed Scopus (52) Google Scholar). Since TH is also the rate-limiting enzyme for catecholamine synthesis (Nagatsu et al., 1964Nagatsu T. Levitt M. Udenfriend S. Conversion of L-tyrosine to 3,4-dihydroxyphenylalanine by cell-free preparations of brain and sympathetically innervated tissues.Biochem Biophys Res Commun. 1964; 14: 543-549Crossref PubMed Scopus (68) Google Scholar), we re-examined for the presence of other enzymes in the catecholamine biosynthesis in melanocytes. Surprisingly, PNMT protein could not be detected under the experimental conditions used. By comparison with TH, staining for DDC and DβH showed only a cytosolic pattern with concentrations towards the periphery of the melanocyte. Clearly, the peri-nuclear site is not occupied. Hence, the soluble cytosolic forms of these enzymes, including TH, implicated autocrine catecholamine synthesis in these cells, as already documented in chromaffin cells of the adrenal medulla and in human epidermal undifferentiated keratinocytes (Pickel et al., 1975Pickel V.M. Joh T.H. Reis D.J. Immunohistochemical localization of tyrosine hydroxylase in brain by light and electron microscopy.Brain Res. 1975; 85: 295-300Crossref PubMed Scopus (71) Google Scholar;Schallreuter et al., 1995Schallreuter K.U. Lemke K.R. Pittelkow M.R. Wood J.M. Körner C. Malik R. Catecholamines in human keratinocyte differentiation.J Invest Dermatol. 1995; 104: 953-957Crossref PubMed Scopus (109) Google Scholar). Hence, the stimulation of melanogenesis by the β2-AR/cAMP signal in melanocytes underlines the symbiotic relationship in the epidermal unit and supports an important role for both melanocytes and keratinocytes in the regulation of pigmentation via cAMP. Nowadays, it is established that cAMP plays a pivotal role in the regulation of skin pigmentation (Abe et al., 1969aAbe K. Butcher R.W. Nicholson W.E. Baird C.E. Liddle R.A. Liddle G.W. Adenosine 3′, 5′-monophosphate (cyclic AMP) as the mediator of the actions of melanocyte stimulating hormone (MSH) and norepinephrine on the frog skin.Endocrinology. 1969; 84: 362-368Crossref PubMed Scopus (95) Google Scholar,Abe et al., 1969bAbe K. Robison G.A. Liddle G.W. Butcher R.W. Nicholson W.E. Baird C.E. Role of cyclic AMP in mediating the effects of MSH, norepinephrine, and melatonin on frog skin color.Endocrinology. 1969; 85: 674-682Crossref PubMed Scopus (120) Google Scholar;Pavel and Schwippelova, 1978Pavel S. Schwippelova Z. Importance of MSH and cyclic 3′,5′-adenosine monophosphate for regulation of melanogenesis (author's transl).Cesk Dermatol. 1978; 53: 57-61PubMed Google Scholar;Thody et al., 1984Thody A.J. Ridley K. Carter R.J. Lucas A.M. Shuster S. Alpha-MSH and coat color changes in the mouse.Peptides. 1984; 5: 1031-1036Crossref PubMed Scopus (21) Google Scholar;Abdel Malek et al., 1986aAbdel Malek Z.A. Hadley M.E. Bregman M.D. Meyskens Jr, F.L. Hruby V.J. Actions of melanotropins on mouse melanoma cell growth in vitro.J Natl Cancer Inst. 1986; 76: 857-863PubMed Google Scholar,Abdel Malek et al., 1986bAbdel Malek Z.A. Kreutzfeld K.L. Hadley M.E. Bregman M.D. Hruby V.J. Meyskens Jr, F.L. Long-term and residual melanotropin-stimulated tyrosinase activity in S91 melanoma cells is density dependent.In Vitro Cell Dev Biol. 1986; 22: 75-81Crossref PubMed Google Scholar;Rees and Flanagan, 1999Rees J.L. Flanagan N. Pigmentation, melanocortins and red hair.Q J Med. 1999; 92: 125-131Crossref Scopus (33) Google Scholar). In this context, it has been reported that binding of α-MSH to the G-protein-coupled melanocortin type 1 receptor (MC1R) involves activation of AC followed by elevation of intracellular cAMP levels, which in turn activates PKA (Pavel and Schwippelova, 1978Pavel S. Schwippelova Z. Importance of MSH and cyclic 3′,5′-adenosine monophosphate for regulation of melanogenesis (author's transl).Cesk Dermatol. 1978; 53: 57-61PubMed Google Scholar;Abdel Malek et al., 1986aAbdel Malek Z.A. Hadley M.E. Bregman M.D. Meyskens Jr, F.L. Hruby V.J. Actions of melanotropins on mouse melanoma cell growth in vitro.J Natl Cancer Inst. 1986; 76: 857-863PubMed Google Scholar). The validity of these results is supported in vivo by patients with MacCune–Albright syndrome displaying large hypopigmented areas caused by a mutation in the Gαs protein in association with decreased cAMP levels (Schwindinger et al., 1992Schwindinger W.F. Francomano C.A. Levine M.A. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune–Albright syndrome.Proc Natl Acad Sci USA. 1992; 89: 5152-5156Crossref PubMed Scopus (432) Google Scholar). Further support stems from the pigmenting effect of α-MSH mimicked in vitro by forskolin, which directly binds and activates AC (Miyazaki et al., 1984Miyazaki K. Goldman M.E. Kebabian J.W. Forskolin stimulates adenylate cyclase activity, adenosine 3′, 5′-monophosphate production and peptide release from the intermediate lobe of the rat pituitary gland.Endocrinology. 1984; 114: 761-766Crossref PubMed Scopus (21) Google Scholar). Taken together, the above observations clearly demonstrate an important role for the cAMP pathway in the regulation of skin pigmentation. So far, this signal was only attributed to the α-MSH/MC1 receptor cascade (Thody et al., 1984Thody A.J. Ridley K. Carter R.J. Lucas A.M. Shuster S. Alpha-MSH and coat color changes in the mouse.Peptides. 1984; 5: 1031-1036Crossref PubMed Scopus (21) Google Scholar;Abdel Malek et al., 1986aAbdel Malek Z.A. Hadley M.E. Bregman M.D. Meyskens Jr, F.L. Hruby V.J. Actions of melanotropins on mouse melanoma cell growth in vitro.J Natl Cancer Inst. 1986; 76: 857-863PubMed Google Scholar;Rees and Flanagan, 1999Rees J.L. Flanagan N. Pigmentation, melanocortins and red hair.Q J Med. 1999; 92: 125-131Crossref Scopus (33) Google Scholar). Based on the results presented herein, the cAMP signal transduction in melanocytes cannot be exclusively invoked from this α-MSH/MCl receptor signal. In this context, it is tempting to revisit the presence of eumelanin biosynthesis in the hair of the pro-opiomelanocortins (POMC) knockout mouse because cAMP production may well have occurred via the β2-AR signal in those murine melanocytes. 1Barsh G: Agouti—past, present and future (abstract). 1st International Workshop on Cutaneous Neuroendocrinology, Hamburg, Germany, 2002. In summary, the discovery of the β2-AR signalling cascade together with cAMP production/melanogenesis in melanocytes adds another source for this important second messenger to the list and provides a new link in control of pigmentation by the catecholamines. Considering that melanocytes exp" @default.
• W2209631778 created "2016-06-24" @default.
• W2209631778 creator A5042445832 @default.
• W2209631778 creator A5070314695 @default.
• W2209631778 creator A5071778263 @default.
• W2209631778 creator A5088536077 @default.
• W2209631778 date "2004-08-01" @default.
• W2209631778 modified "2023-10-16" @default.
• W2209631778 title "Autocrine Catecholamine Biosynthesis and the β2-Adrenoceptor Signal Promote Pigmentation in Human Epidermal Melanocytes" @default.
• W2209631778 cites W1763096406 @default.
• W2209631778 cites W1965156718 @default.
• W2209631778 cites W1967092942 @default.
• W2209631778 cites W1971526475 @default.
• W2209631778 cites W1976426993 @default.
• W2209631778 cites W1978531872 @default.
• W2209631778 cites W1980480871 @default.
• W2209631778 cites W1985264276 @default.
• W2209631778 cites W1991218053 @default.
• W2209631778 cites W1993664335 @default.
• W2209631778 cites W1993961428 @default.
• W2209631778 cites W1997546689 @default.
• W2209631778 cites W1997925504 @default.
• W2209631778 cites W2000682588 @default.
• W2209631778 cites W2006212841 @default.
• W2209631778 cites W2010390522 @default.
• W2209631778 cites W2015445020 @default.
• W2209631778 cites W2017925303 @default.
• W2209631778 cites W2029785826 @default.
• W2209631778 cites W2029962727 @default.
• W2209631778 cites W2048626660 @default.
• W2209631778 cites W2059132314 @default.
• W2209631778 cites W2061343115 @default.
• W2209631778 cites W2062841786 @default.
• W2209631778 cites W2063907656 @default.
• W2209631778 cites W2072512993 @default.
• W2209631778 cites W2075025771 @default.
• W2209631778 cites W2075304570 @default.
• W2209631778 cites W2080419647 @default.
• W2209631778 cites W2080875376 @default.
• W2209631778 cites W2091161222 @default.
• W2209631778 cites W2094807512 @default.
• W2209631778 cites W2097450722 @default.
• W2209631778 cites W2097979581 @default.
• W2209631778 cites W2123454868 @default.
• W2209631778 cites W2134549833 @default.
• W2209631778 cites W2163479796 @default.
• W2209631778 cites W4250684467 @default.
• W2209631778 cites W4250928742 @default.
• W2209631778 cites W1976127327 @default.
• W2209631778 doi "https://doi.org/10.1111/j.0022-202x.2004.23210.x" @default.
• W2209631778 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/15245435" @default.
• W2209631778 hasPublicationYear "2004" @default.
• W2209631778 type Work @default.
• W2209631778 sameAs 2209631778 @default.
• W2209631778 citedByCount "96" @default.
• W2209631778 countsByYear W22096317782012 @default.
• W2209631778 countsByYear W22096317782013 @default.
• W2209631778 countsByYear W22096317782014 @default.
• W2209631778 countsByYear W22096317782015 @default.
• W2209631778 countsByYear W22096317782016 @default.
• W2209631778 countsByYear W22096317782017 @default.
• W2209631778 countsByYear W22096317782018 @default.
• W2209631778 countsByYear W22096317782019 @default.
• W2209631778 countsByYear W22096317782020 @default.
• W2209631778 countsByYear W22096317782021 @default.
• W2209631778 countsByYear W22096317782022 @default.
• W2209631778 countsByYear W22096317782023 @default.
• W2209631778 crossrefType "journal-article" @default.
• W2209631778 hasAuthorship W2209631778A5042445832 @default.
• W2209631778 hasAuthorship W2209631778A5070314695 @default.
• W2209631778 hasAuthorship W2209631778A5071778263 @default.
• W2209631778 hasAuthorship W2209631778A5088536077 @default.
• W2209631778 hasBestOaLocation W22096317781 @default.
• W2209631778 hasConcept C107538193 @default.
• W2209631778 hasConcept C126322002 @default.
• W2209631778 hasConcept C128240485 @default.
• W2209631778 hasConcept C134018914 @default.
• W2209631778 hasConcept C170493617 @default.
• W2209631778 hasConcept C185592680 @default.
• W2209631778 hasConcept C2775894120 @default.
• W2209631778 hasConcept C2777658100 @default.
• W2209631778 hasConcept C2779769559 @default.
• W2209631778 hasConcept C502942594 @default.
• W2209631778 hasConcept C55493867 @default.
• W2209631778 hasConcept C71924100 @default.
• W2209631778 hasConcept C86803240 @default.
• W2209631778 hasConcept C95444343 @default.
• W2209631778 hasConceptScore W2209631778C107538193 @default.
• W2209631778 hasConceptScore W2209631778C126322002 @default.
• W2209631778 hasConceptScore W2209631778C128240485 @default.
• W2209631778 hasConceptScore W2209631778C134018914 @default.
• W2209631778 hasConceptScore W2209631778C170493617 @default.
• W2209631778 hasConceptScore W2209631778C185592680 @default.
• W2209631778 hasConceptScore W2209631778C2775894120 @default.
• W2209631778 hasConceptScore W2209631778C2777658100 @default.
• W2209631778 hasConceptScore W2209631778C2779769559 @default.
• W2209631778 hasConceptScore W2209631778C502942594 @default.
• W2209631778 hasConceptScore W2209631778C55493867 @default.

• next