Involvement of Protein Kinase Cδ/Extracellular Signal-regulated Kinase/Poly(ADP-ribose) Polymerase-1 (PARP-1) Signaling Pathway in Histamine-induced Up-regulation of Histamine H1 Receptor Gene Expression in HeLa Cells

Mizuguchi, Hiroyuki; Terao, T.; Kitai, Mika; Ikeda, Mitsuhiro; Yoshimura, Yoshiyuki; Das, Asish Kumar; Kitamura, Yoshiaki; Takeda, Noriaki; Fukui, Hirokazu

doi:10.1074/jbc.m111.253104

Cited by 60 publications

(66 citation statements)

References 59 publications

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“…Rottlerin has been used to confirm the possible role of PKCδ isoform in several signaling pathways. Moreover, the results obtained with rottlerin were compatible with those obtained utilizing more selective approaches to inhibit PKCδ in a previous report (17). It was recently reported rottlerin also inhibited PKCθ (23).…”

Section: Discussionsupporting

confidence: 79%

“…We showed that treatment with PMA significantly increased glucagon secretion from isolated islets and quercetin treatment suppressed the PMA-induced increase in glucagon secretion in α-cells. We reported that quercetin suppressed PMA-induced Tyr 311 phosphorylation of PKCδ in HeLa cells (17). In the present study, we showed that quercetin also suppressed PMA-induced Tyr 311 phosphorylation of PKCδ in isolated islets.…”

Section: Discussionsupporting

confidence: 65%

“…We have demonstrated that PKCδ signaling is involved in PMAinduced upregulation of histamine H1 receptor (H1R) gene expression in HeLa cells and compounds, including quercetin and (-)-maackiain, suppressed H1R gene expression through the inhibition of PKCδ signaling (17)(18)(19). Thus, suppression of PKCδ signaling by these compounds could improve diabetic symptoms and help to further elucidate the mechanisms underlying these actions to better understand the role of PKCδ signaling in diabetes onset and progression.…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

et al. 2017

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: Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca 2+ -dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr 311 of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

et al. 2017

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“…Next, we investigated the effect of these antihistamines on H1R gene expression in HeLa cells. We previously found that the protein kinase Cδ (PKCδ) / extracellularregulated kinase / poly (ADP-ribose) polymerase-1 signaling pathway is involved in H1R gene expression in HeLa cells and that pretreatment with rottlerin, a selective PKCδ inhibitor, completely blocks this pathway (15). Pretreatment with 5 μM rottlerin significantly decreased basal H1R gene expression to 60% of the control level, indicating that there is constitutive H1R activation in HeLa cells (Fig.…”

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confidence: 99%

Inverse Agonistic Activity of Antihistamines and Suppression of Histamine H1 Receptor Gene Expression

et al. 2012

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Pollinosis is a seasonal allergic rhinitis caused by hypersensitivity to tree or grass pollens, which affects more than 36 million people in the U.S. and about 16% of the Japanese population (1, 2). Histamine is a major chemical mediator involved in allergic reactions. Its actions are mainly mediated by the histamine H 1 receptor (H1R) and H1R activation results in the symptoms of allergic rhinitis.It has been reported that expression of H1R mRNA is increased in patients with allergic rhinitis (3,4). We have demonstrated that intranasal application of toluene-2,4-diisocyanate (TDI) induces histamine release from mast cells via neurogenic inflammation and causes nasal hypersensitivity in rats (5), with H1R expression being up-regulated at both the mRNA and protein levels in the nasal mucosa of TDI-sensitized rats (6). We have also demonstrated that the level of H1R expression is strongly correlated with the severity of allergy symptoms in TDIsensitized rats and in patients with pollinosis (7), while agents that suppress H1R gene up-regulation alleviate allergy symptoms (8, 9). These findings, combined with the report that the strength of H1R signaling depends on the level of expression of this receptor (10), suggest that H1R is an allergy-sensitive gene and that its expression influences the severity of allergy symptoms. Therefore, drugs targeting the signaling pathway involved in histamine-induced up-regulation of H1R gene expression could be useful for treating allergic diseases.Antihistamines are widely employed as the first-line treatment for nasal symptoms of pollinosis because these drugs are thought to antagonize histamine and prevent it from binding to the H1R. According to the two-state model, however, the active and inactive states of a receptor exist in equilibrium, so antihistamines could act as inverse agonists that combine with and stabilize the inactive form of H1R to shift the equilibrium toward the inactive state and down-regulate constitutive receptor activity, even in the absence of histamine (11). Therefore, antihistamines might not only antagonize histamine by blocking its binding with the H1R, but could also suppress constitutive H1R activity. Although the clinical importance of constitutive activity has not been clarified, it can be hypothesized that inverse agonists would more potently alleviate allergic symptoms than neutral antagonists by inhibiting constitutive activity. However, the influence of the inverse agonistic activity of antihistamines on H1R gene expression has not been evaluated.We previously demonstrated that histamine stimulates up-regulation of H1R gene expression in HeLa cells that endogenously express this receptor (6). In the present study, we examined the effect of inverse agonists on upregulation of H1R gene expression by HeLa cells. Our Tokushima 770-8505, Japan Received September 29, 2011; Accepted November 15, 2011 Abstract. Histamine H 1 receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R g...

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“…The mechanism of LT-mediated up-regulation of H1R is unknown, although histamine up-regulates the expression of H1R mRNA in HeLa cells through protein kinase C (PKC)-mediated H1R gene transcription (10). However it was reported that treatment of OVAsensitized mice with PKC inhibitors (GF109203X and rottlerin) before provocation diminished not only the CysLT production but also the effects of LT such as eosinophil infiltration and AHR (11), suggesting the involvement of PKC in the LT signaling pathway.…”

Section: Combination Of Leukotorienementioning

confidence: 99%

Combination of Leukotoriene Receptor Antagonist With Antihistamine Has an Additive Suppressive Effect on the Up-regulation of H1-Receptor mRNA in the Nasal Mucosa of Toluene 2,4-Diisocyanate-Sensitized Rat

et al. 2013

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Abstract. An attempt was made to clarify the additive suppressive effects of pranlukast, a cysteinyl leukotriene-receptor (LTR) antagonist, in combination with chlorpheniramine, an antihistamine, on the up-regulation of histamine H 1 -receptor (H1R) mRNA in toluene 2,4-diisocyanate (TDI)-sensitized rats. Although pre-treatment with pranlukast partially, but significantly, suppressed TDI-induced up-regulation of H1R mRNA and nasal symptoms, pre-treatment with the combination of pranlukast and chlorpheniramine significantly suppressed them in a manner greater than either drug alone. These findings suggest that the additive therapeutic effect of the combination of LTR antagonist and antihistamine is due to their additive suppression of H1R up-regulation.

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Involvement of Protein Kinase Cδ/Extracellular Signal-regulated Kinase/Poly(ADP-ribose) Polymerase-1 (PARP-1) Signaling Pathway in Histamine-induced Up-regulation of Histamine H1 Receptor Gene Expression in HeLa Cells

Cited by 60 publications

References 59 publications

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets

Inverse Agonistic Activity of Antihistamines and Suppression of Histamine H1 Receptor Gene Expression

Combination of Leukotoriene Receptor Antagonist With Antihistamine Has an Additive Suppressive Effect on the Up-regulation of H1-Receptor mRNA in the Nasal Mucosa of Toluene 2,4-Diisocyanate-Sensitized Rat

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