Increased Cholera Toxin-, and Forskolin-induced Cyclic AMP Accumulations in Psoriatic Involved Versus Uninvolved or Normal Human Epidermis

Iizuka, Hajime; Matsuo, Shinobu; Tamura, Toshiya; Ohkuma, Noritaka

doi:10.1111/1523-1747.ep12464401

Cited by 32 publications

(12 citation statements)

References 19 publications

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“…Sustained activation of PKC has been assumed in psoriatic hyperproliferative epidermis [7,14]. We have reported that both cholera toxin-induced and forskolin-induced cyclic AMP accumulations are increased in psoriatic hyperproliferative epidermis [15]. Again, forskolin-induced cyclic AMP accumulation was more marked than cholera toxin-induced cyclic AMP accumulation.…”

Section: Discussionmentioning

confidence: 82%

“…We have reported that phorbol esters decrease the ~2-adrenergic as well as other stimulatory receptor adenylate cyclase responses of pig epidermis [15,16]. We have reported that phorbol esters decrease the ~2-adrenergic as well as other stimulatory receptor adenylate cyclase responses of pig epidermis [15,16].…”

Section: Discussionmentioning

confidence: 82%

“…Cholera toxin stimulates Gs by ADP ribosylation of its subunit and activates adenylate cyclase, while forskolin directly stimulates adenylate cyclase [3,15]. PMA-or OAG-treated FRSK showed a significant decrease in cholera toxin-induced cyclic AMP accumulation (Figs.…”

Section: Resultsmentioning

confidence: 93%

“…It has been well established that the epidermis contains both Gs~ and Gic~ (Gi2c~ and Gi3~) [5,34,36], and various stimulatory receptor systems [15,35] including the 132-adrenergic, Wostaglandin E2, adenosine and histamine (H2) receptor systems.…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase C-dependent modulation of stimulatory guanine nucleotide binding protein of fetal rat skin keratinocytes

1996

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Although the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA) has been known to induce heterologous desensitization of the epidermal adenylate cyclase, the precise mechanism of PMA action remains unknown. Effects of PMA on the receptor-G-protein-adenylate cyclase system of fetal rat skin keratinocytes (FRSK) were investigated. Choleratoxin catalysed the ADP ribosylation of 45 kDa and 52 kDa membrane proteins and islet activating protein (IAP) catalysed the ADP ribosylation of a 40 kDa membrane protein. Incubation of FRSK with PMA decreased the cholera toxin-catalysed ADP ribosylation of the membrane protein, but not the IAP-catalysed ADP ribosylation. The effect of PMA on the cholera toxin-catalysed ADP ribosylation was inhibited by the PKC inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methyl piperazine dihydrochloride). 1-Oleoyl-2-acetylglycerol (OAG), a membrane-permeable diacylglycerol analogue, also decreased the cholera toxin-catalysed ADP ribosylation, but 4-0-methyl PMA, a very weak PKC activator, had no effect. Keratinocytes are known to express the guanine nucleotide binding proteins, Gsalpha, Gi2alpha, and Gi3alpha. Immunoblot analysis of the PMA-treated FRSK showed no detectable difference in the amount of Gsalpha, Gi2alpha, Gi3alpha, or the beta subunit of the G-protein. PMA significantly decreased the beta-adrenergic adenylate cyclase response and cholera toxin-induced cyclic AMP accumulation, while it markedly increased forskolin-induced cyclic AMP accumulation. These results indicate that phorbol esters affect the stimulatory guanine nucleotide binding protein (Gs) of FRSK via a PKC-dependent pathway.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Protein kinase C-dependent modulation of stimulatory guanine nucleotide binding protein of fetal rat skin keratinocytes

1996

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“…Yet, further studies revealed a difference in responsiveness to β-adrenergic stimulation between psoriatic and normal epidermis suggestive of aberrant cAMP production [60] and that β-adrenergic rather than prostaglandin (PGE) E2 stimulation [61] was affected. These observations are not limited to β adrenergic signaling; differences in intracellular cAMP accumulation induced by various tmAC agonists (e.g., cholera toxin, forskolin) were also observed in psoriatic versus uninvolved or normal epidermis [62]. In addition, several studies have also reported deficiencies in cAMP effectors, including decreased expression of and cAMP binding to PKA in psoriatic fibroblasts and erythrocytes [9], which appears responsive to retinoid treatment [63,64] and has been hypothesized to result from altered posttranslational modification of PKA [65,66] or oxidative states in these cells [67].…”

Section: Camp Signaling In Psoriasismentioning

confidence: 80%

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

Levy¹,

Zhou²

2015

J Clin Exp Dermatol Res

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The second messenger cyclic adenosine monophosphate (cAMP) regulates numerous key pathways that impact the immune system. Distinct cellular cAMP signaling pathways can lead to both pro-and anti-inflammatory effects depending upon the cell type. When dysregulated, these cAMP pathways can influence the pathogenesis of inflammatory cutaneous diseases, such as atopic dermatitis and psoriasis. In psoriasis and atopic dermatitis, cAMP and/or its effector proteins (e.g., protein kinase A) are downregulated suggesting that elevation of cAMP might be a therapeutic option. cAMP levels are the result of balance between synthesis by adenylyl cyclases and degradation by phosphodiesterases (PDEs). Pharmacologically inhibiting PDEs represents one effective mechanism to raise intracellular cAMP levels perhaps leading to targeted immune suppression. Several drugs have been developed to target PDEs and while some toxicities (e.g., nausea and emesis) exist these drugs are generally well tolerated. Perhaps the best characterized is Apremilast, a PDE4 specific inhibitor, which has been FDA approved for the treatment of psoriasis and shows great promise as a safe and novel immunosuppressive medication. Following on the heels of Apremilast are numerous oral and topical PDE inhibitors in various stages of clinical trials. In this review, we examine the role of cAMP signaling in inflammatory cutaneous diseases and the development of PDE inhibitors as therapeutics.

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?-Adrenergic receptors in psoriasis: evidence for down-regulation in lesional skin

et al. 1993

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Lesional psoriatic skin displays reduced responsiveness to beta-adrenergic stimulating agents. To elucidate whether the receptor protein itself is responsible for this, lesional and non-lesional psoriatic skin was investigated ex vivo for maximal beta-adrenergic binding density (Bmax) and beta-adrenergic binding affinity (KD). Epidermal crude membrane homogenates (ECMH) were prepared from split-thickness skin biopsies and saturated with the lipophilic beta-adrenergic antagonist (-)-125I-iodocyanopindolol (ICYP) as radioligand. Specific binding was saturable and Scatchard transformation of the binding data revealed a homogeneous class of beta-adrenergic receptors in all nine experiments. The maximal beta-adrenergic binding density was significantly less in lesional than in non-lesional psoriatic skin (Bmax = 49.7 +/- 7.2 fmol/mg protein vs. 67.1 +/- 2.2 fmol/mg protein, n = 9, P < 0.05). The binding affinity was similar in lesional and in non-lesional skin (KD = 9.0 +/- 1.5 pmol/l vs. 8.0 +/- 0.9 pmol/l). These results could at least partially explain the reduced responsiveness of the beta-adrenergic system in lesional psoriatic skin seen after stimulation with beta-adrenergic agonists.

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Increased Cholera Toxin-, and Forskolin-induced Cyclic AMP Accumulations in Psoriatic Involved Versus Uninvolved or Normal Human Epidermis

Cited by 32 publications

References 19 publications

Protein kinase C-dependent modulation of stimulatory guanine nucleotide binding protein of fetal rat skin keratinocytes

Protein kinase C-dependent modulation of stimulatory guanine nucleotide binding protein of fetal rat skin keratinocytes

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

?-Adrenergic receptors in psoriasis: evidence for down-regulation in lesional skin

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