Beta-Adrenergic Stimulation Induces Intracellular Ca++ Increase in Human Epidermal Keratinocytes

Koizumi, Hiroko; Yasui, Chikako; Fukaya, Takeshi; Ohkawara, Akira; Ueda, Tetsuo

doi:10.1111/1523-1747.ep12462120

Cited by 57 publications

(31 citation statements)

References 22 publications

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“…The expression of these receptors on keratinocytes are regulated by extracellular levels of calcium [12] as well as by 6-biopterin, the redox product of 6BHR, which is increased in the epidermis in patients with vitiligo (reviewed in [13,61]). Since beta2AR activation by catecholamines also induces calcium influx into keratinocytes [14], one might have anticipated that intracellular calcium levels are increased in keratinocytes in vitiliginous epidermis. However, a defect in calcium influx has been demonstrated in keratinocytes derived from involved vitiliginous epidermis [62], although this data may be represented by a limited number of patient samples.…”

Section: Vitiligo and Beta2armentioning

confidence: 99%

“…Stimulation of the beta2AR leads to a transient increase in the keratinocyte intracellular calcium concentration [14], and this likely occurs through several signaling cascades ( Figure 1). Activation of the cAMP-dependent pathway by direct activation of adenylate cyclase has been shown to reproduce the increase in intracellular calcium that is seen with ligand stimulation of the beta2AR [15,16].…”

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confidence: 99%

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Beta Adrenergic Receptors in Keratinocytes

Sivamani

Lam

Isseroff

2007

Dermatologic Clinics

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SynopsisBeta2 adrenergic receptors were identified in keratinocytes more than 30 years ago, but their function in the epidermis continues to be elucidated. Abnormalities in their expression, signaling pathway, or in the generation of endogenous catecholamine agonists by keratinocytes have been implicated in the pathogenesis of cutaneous diseases such as atopic dermatitis, vitiligo and psoriasis. New studies also indicate that the beta2AR also modulates keratinocyte migration, and thus can function to regulate wound re-epithelialization. This review focuses on the function of these receptors in keratinocytes and their contribution to cutaneous physiology and disease.Keywords beta-adrenergic; keratinocyte; atopic dermatitis; psoriasis; vitiligo; wound Physiology of the beta2 adrenergic receptor in keratinocytesOf the several identified classes of adrenergic receptors (alpha and beta, and their subtypes), it is of particular interest to note that human keratinocytes, the cells the make up the majority of the epidermis, express only beta2 adrenergic receptors (beta2AR) [1][2][3][4]. The beta adrenergic receptor is a classic seven transmembrane G protein coupled receptor. These receptors serve as the endogenous receptor to the catecholamine hormones norepinephrine and epinephrine, and can be further subdivided into beta1, beta2, and beta3 subtypes, based on their differential pharmacological response to catecholamines and specific antagonists, as well as differences in their protein sequences [5][6][7].The first studies to suggest the presence of betaAR in the epidermis were functional ones that demonstrated an increase in levels of cAMP in keratinocytes after stimulation with non-specific betaAR agonists [8,9]. Subsequently, work using agonists and antagonists with specificity for the different adrenergic receptor subtypes demonstrated that the increase in keratinocyte

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Section: Vitiligo and Beta2armentioning

confidence: 99%

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confidence: 99%

Beta Adrenergic Receptors in Keratinocytes

Sivamani

Lam

Isseroff

2007

Dermatologic Clinics

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“…Here, we have shown that HaCaT cells treated with this agent developed greatly enhanced levels of four markers of terminal differentiation [21][22][23]: keratins K1 and K10, involucrin and transglutaminase, suggesting that cAMP influences the differentiation of normal human keratinocytes. Since human keratinocytes possess ß-adrenergic receptors that increase intracellular adenylate cyclase when activated [24], ß-adrenergic receptor agonists can be used to increase keratinocyte intracellular cAMP levels. Therefore we further substantiate the role of this pathway in differentiation by elevating intracellular cAMP by the simultaneous treatment of cells with a phosphodiesterase inhibitor, IBMX, and a ß-adrenergic receptor agonist, isoproterenol.…”

Section: The Differentiation Of the Keratinocyte Is Camp-dependentmentioning

confidence: 99%

The Induction of Terminal Differentiation Markers by the cAMP Pathway in Human HaCaT Keratinocytes

Mammone

Marenus

Maes

et al. 1998

Skin Pharmacol Physiol

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The terminal differentiation of human epidermal keratinocytes is a complex morphological and biochemical shift from a mitotically active cell to an inert protein cross-linked envelope. This transition is a clearly predetermined cell death mechanism, but it is unlike many other programmed cell deaths in that it is not apoptotic. To explore and contrast the mechanism by which keratinocytes are committed to differentiation rather than apoptosis, we focused on the cyclic adenosine monophosphate (cAMP) signaling pathway using selective modulators of intracelluar cAMP levels. Markers of differentiation were assayed by Western blotting. Raising intracelluar cAMP levels by treating HaCaT cells with forskolin, a diterpene, or with isobutylmethylxanthine, a phosphodiesterase inhibitor, and isoproterenol, a β-adrenergic receptor agonist that selectively activates adenylate cyclase, increased the levels of the differentiation markers keratin K1 and K10, involucrin and transglutaminase. H89 and KT5720, both inhibitors of cAMP-dependent protein kinase, suppressed the expression of keratins K1 and K10. These observations are in line with the defined role for cAMP in the control of keratinocyte differentiation.

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“…genetic, neural, endocrine) component, together with physical, emotional and environmental stress, for trig gering a reaction which could be sufficient to precipitate 'illness' [13,14], Since kératinocytes in the human epider mis have the capacity of the total catecholamine biosyn thetic pathway [15], including the entire pathway for de novo synthesis and recycling of the essential cofactor (6R)5, 6, 7, 8-tetrahydrobiopterin for the enzymes tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan mono-oxygenase, it seemed plausible that this neuroendo crine system could be of significance in vitiligo [1,2]. Kératinocytes also express (3,-adrenoceptors in high density with significant higher numbers in undifferentiated/differentiating compared to differentiated cells [16][17][18], Koi zumi et al [19] observed an increase in intracellular cal cium upon adrenergic stimulation of the [3,-adrenoceptors in these cells. Using the isotope J5Ca, it has been shown that this increase correlated with an extracellular influx [16], Based on these new observations, it can be concluded that the epidermis has the capacity of an autocrine organ.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Personality Structure in Patients with Vitiligo and a Possible Association with Impaired Catecholamine Metabolism

Salzer

Schallreuter²

1995

Dermatology

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Background: Patients with vitiligo show an increased β₂-adrenoceptor density in differentiating vitiliginous keratinocytes correlating with a defective extracellular calcium uptake. Thirty-one percent of the patients present increased norepi-nephrine levels in their urine and 98% in their plasma. Objective: The aim of this study was to find out whether these patients may: (a) have a characteristic personality structure and/or (b) show an increased stress sensitivity towards physical/environmental/hormonal changes in association with a defective catecholamine metabolism. Methods and Results: The investigation included a randomized group of 117 patients with vitiligo (89 female, 28 male). Catecholamines were determined in plasma in a random sample of the total group (n = 30, M/F= 10/20). Norepinephrine levels in plasma were significantly higher compared to controls, whereas epinephrine was within the normal range. No specific personality pattern was found although divergencies from the normal healthy control were observed in 5 out of 12 personality dimensions. Moderate to intolerable disfigurement and psychological disturbance were stated by 75% of the patients. Evaluation of the educational status revealed that 26.5% of the patients graduated successfully from university compared to 8.4% in the normal population. Conclusion: The results of this study suggest a possible link between cate-cholamine-based stress and a genetic susceptibility to the onset/progression of this depigmentation disorder.

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Beta-Adrenergic Stimulation Induces Intracellular Ca++ Increase in Human Epidermal Keratinocytes

Cited by 57 publications

References 22 publications

Beta Adrenergic Receptors in Keratinocytes

Beta Adrenergic Receptors in Keratinocytes

The Induction of Terminal Differentiation Markers by the cAMP Pathway in Human HaCaT Keratinocytes

Investigation of the Personality Structure in Patients with Vitiligo and a Possible Association with Impaired Catecholamine Metabolism

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