Involvement of multiple PKC isoforms in phorbol 12,13-dibutyrate-induced contraction during high K+ depolarization in bronchial smooth muscle of mice

Sakai, Hiroyasu; Kurihara, Yusuke; Hashimoto, Yuki; Chiba, Yoshihiko; Misawa, Miwa

doi:10.1540/jsmr.46.225

Cited by 9 publications

(9 citation statements)

References 24 publications

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“…Ca 2+ sensitization by both phorbol esters and thrombin was also evident in nonpermeabilized lung slices, where both PMA and thrombin markedly potentiated the response to KCl. Consistent with our results, a potentiation of phorbol ester–induced airway contraction by KCl-induced membrane depolarization was reported previously (Sakai et al, 2010). We estimate that agonists that cause membrane depolarization will increase airway resistance four times more in airways that have been exposed to agents like thrombin that activate PKC than in airways that have not been exposed to such agents.…”

Section: Discussionsupporting

confidence: 94%

“…For example, phorbol esters induce relaxation in guinea pig trachea rings (Huang et al, 1987; Souhrada and Souhrada, 1989; Morrison and Vanhoutte, 1991), initiate a biphasic response (a transient relaxation followed by a sustained contraction) in human bronchus (Yang and Black, 1995), and stimulate the contraction of isolated human bronchial SMCs (Rossetti et al, 1995). There are no significant contractile responses to phorbol esters in rat tracheal smooth muscle (Peiper et al, 1996) or mouse bronchial rings (Sakai et al, 2010). PMA-induced airway contraction is significantly increased by co-stimulation with KCl in all species studied, including mice and rats (Sakai et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…There are no significant contractile responses to phorbol esters in rat tracheal smooth muscle (Peiper et al, 1996) or mouse bronchial rings (Sakai et al, 2010). PMA-induced airway contraction is significantly increased by co-stimulation with KCl in all species studied, including mice and rats (Sakai et al, 2010). Our results in small airways show that exposure of mouse lung slices to phorbol esters (PMA and PDBu) induced transient and asynchronous small airway SMC contractions (SMC twitching) that resulted in a very small decrease in airway lumen area.…”

Section: Discussionmentioning

confidence: 99%

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Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Mukherjee

Trice

Shinde

et al. 2013

Journal of General Physiology

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Protein kinase C (PKC) has been implicated in the regulation of smooth muscle cell (SMC) contraction and may contribute to airway hyperresponsiveness. Here, we combined optical and biochemical analyses of mouse lung slices to determine the effects of PKC activation on Ca2+ signaling, Ca2+ sensitivity, protein phosphorylation, and contraction in SMCs of small intrapulmonary airways. We found that 10 µM phorbol-12-myristate-13-acetate or 1 µM phorbol 12,13-dibutyrate induced repetitive, unsynchronized, and transient contractions of the SMCs lining the airway lumen. These contractions were associated with low frequency Ca2+ oscillations in airway SMCs that resulted from Ca2+ influx through L-type voltage-gated Ca2+ channels and the subsequent release of Ca2+ from intracellular stores through ryanodine receptors. Phorbol ester stimulation of lung slices in which SMC intracellular Ca2+ concentration ([Ca2+]i) was “clamped” at a high concentration induced strong airway contraction, indicating that PKC mediated sensitization of the contractile response to [Ca2+]i. This Ca2+ sensitization was accompanied by phosphorylation of both the PKC-potentiated PP1 inhibitory protein of 17 kD (CPI-17) and the regulatory myosin light chain. Thrombin, like the phorbol esters, induced a strong Ca2+ sensitization that was inhibited by the PKC inhibitor GF-109203X and also potentiated airway contraction to membrane depolarization with KCl. In conclusion, we suggest that PKC activation in small airways leads to both the generation of Ca2+ oscillations and strong Ca2+ sensitization; agents associated with airway inflammation, such as thrombin, may activate this pathway to sensitize airway smooth muscle to agonists that cause membrane depolarization and Ca2+ entry and induce airway hyperresponsiveness.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Mukherjee

Trice

Shinde

et al. 2013

Journal of General Physiology

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show abstract

“…Ca 2+ sensitization by both phorbol esters and thrombin was also evident in nonpermeabilized lung slices, where both PMA and thrombin markedly potentiated the response to KCl. Consistent with our results, a potentiation of phorbol ester-induced airway contraction by KCl-induced membrane depolarization was reported previously (Sakai et al, 2010). We estimate that agonists generate low frequency Ca 2+ oscillations and SMC twitching.…”

Section: Pkc Activation Induces Small Airway Smc Twitchingsupporting

confidence: 93%

Ca²⁺oscillations, Ca²⁺sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Mukherjee¹,

Trice²,

Shinde³

et al. 2013

J Cell Biol

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“…PKC is a generic term used to describe the largest serine/threonine directed kinase subfamily currently known [22]. Studies suggest that mechanical ventilation can lead to the elevation of intracellular Ca 2+ , then induce the activation of PKC, eventually activating c-fos causing lung injury [23].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the tight junction protein occludin: effects on ventilation-induced lung injury and mechanisms of action

Liu

Wang

2014

BMC Pulm Med

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BackgroundOccludin, a tight junction protein, plays an important role in maintaining the integrity of the lung epithelial barrier; however, its role in ventilation-induced lung injury has not been explored. Here, we measured the expression of occludin with different tidal volumes. Our study indicated that the level of occludin was significantly decreased and alveolar permeability was increased owing to acute lung injury.MethodsThirty healthy Wistar rats (15 female, 15 male) weighing 250–300 g, were randomly divided into 5 groups (n = 6 in each group): a control group (group C), a low tidal volume group (group L), a low tidal volume + protein kinase C(PKC) inhibitor group (group L + P), a high tidal volume group (group H) and a high tidal volume + PKC inhibitor group (group H + P). Tracheas of rats in the control group underwent incision without any special treatment. The other four groups were mechanically ventilated for 4 h. The rats in groups L + P and H + P were treated with a PKC inhibitor (bisindolylmaleimide I, 0.12 mg/kg) by intramuscular injection 1 h before anesthesia. Rats were sacrificed after mechanical ventilation. Specimens of lung tissues were harvested. Lung pathological changes were observed using an optical microscope, and lung wet/dry weight ratio was measured. The occludin protein level was assayed by immunohistochemistry and Western blotting.ResultsHE staining and immunohistochemistry results showed that occludin was mainly located in alveolar epithelial cells and some alveolar endothelial cells. The lung injury and alveolar edema were more serious in high tidal volume groups than in low tidal volume groups. Occludin expression was reduced and PKC activation was increased in rats in the high tidal volume groups compared with rats in the low tidal volume groups. Rats that were pretreated with the PKC inhibitor had less pulmonary edema induced by the high tidal volume ventilation.ConclusionMechanical ventilation can activate the PKC signaling pathway and tight junction proteins participate in this pathway. Up-regulation of occludin can reduce ventilation-induced lung injury.

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Involvement of multiple PKC isoforms in phorbol 12,13-dibutyrate-induced contraction during high K+ depolarization in bronchial smooth muscle of mice

Cited by 9 publications

References 24 publications

Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Ca²⁺oscillations, Ca²⁺sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Upregulation of the tight junction protein occludin: effects on ventilation-induced lung injury and mechanisms of action

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Involvement of multiple PKC isoforms in phorbol 12,13-dibutyrate-induced contraction during high K+ depolarization in bronchial smooth muscle of mice

Cited by 9 publications

References 24 publications

Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Ca2+oscillations, Ca2+sensitization, and contraction activated by protein kinase C in small airway smooth muscle

Upregulation of the tight junction protein occludin: effects on ventilation-induced lung injury and mechanisms of action

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Ca²⁺oscillations, Ca²⁺sensitization, and contraction activated by protein kinase C in small airway smooth muscle