Regulation of GPCR-mediated smooth muscle contraction: Implications for asthma and pulmonary hypertension

Wright, Donna; Tripathi, Sandeep Kumar; Sikarwar, Anurag Singh; Santosh, Kanakappan; Perez‐Zoghbi, Jose F.; Ojo, O. O.; Irechukwu, N; Ward, Jeremy P. T.; Schaafsma, Dedmer

doi:10.1016/j.pupt.2012.06.005

Cited by 39 publications

(36 citation statements)

References 171 publications

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“…The major mechanisms by which elevation of [Ca 2ϩ ] i occurs in ASM in response to agonist have been recently reviewed (17,145,186,231,261,278,285,335). Although there are species differences in the contribution of specific pathways, some common mechanisms are well recognized.…”

Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

179

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

179

154

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“…CPI-17 is a downstream target of both PKC and Rho kinase in ASM (43). CPI-17 inhibits MLCP and leads to MLC 20 phosphorylation and subsequent contraction.…”

Section: Mlck/mlcp In Contraction and Relaxation-role For Accessory Pmentioning

confidence: 99%

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Townsend

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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b-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate b-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with b-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 mM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C b enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C b activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate b-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with b-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.Keywords: asthma; adrenergic receptor; myosin light chain; lung; bronchodilation Clinical RelevanceNatural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonist-induced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.

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“…Ca 2+ entry through store-operated Ca 2+ channels replenishes the Ca 2+ stores, thereby maintaining Ca 2+ oscillations and sustained airway contraction during prolonged agonist stimulation (Perez and Sanderson, 2005 (Bai and Sanderson, 2006b;Perez-Zoghbi and Sanderson, 2007). Most agonists that stimulate airway contraction are ligands of G protein-coupled receptors that signal through G q/11 and G 12/13 and consequently activate both PKC and RhoA kinase (ROK) in SMCs, respectively (Wright et al, 2012). In the small airways, inhibitors of PKC or ROK inhibit ACh-induced Ca 2+ sensitization (Bai and Sanderson, 2006b).…”

Section: Preparation Of Lung Slicesmentioning

confidence: 99%

“…PKC activity induces phosphorylation of CPI-17 and increases phosphorylated rMLC in small airways CPI-17, a specific target of PKC, is almost exclusively expressed in smooth muscle; when phosphorylated, CPI-17 inhibits MLCP (Wright et al, 2012). We used Western blot analysis to detect and measure phosphorylation of CPI-17 and rMLC in small airways.…”

Section: Pma and Thrombin Potentiated Airway Contraction Induced By Mmentioning

confidence: 99%

“…The phosphoprotein CPI-17, mainly expressed in smooth muscle, is a target for PKC that, when phosphorylated, binds to the PP1 subunit of MLCP to cause its inhibition, thereby causing Ca 2+ sensitization (Wright et al, 2012). Here, we found that PKC activation induces 60% phosphorylation of CPI-17 in the airways of "normal" and "Ca 2+ -permeabilized" lung slices, suggesting that CPI-17 is a mediator of PMA-induced Ca 2+ sensitization in small airways.…”

Section: Pkc Activation Induces Small Airway Smc Twitchingmentioning

confidence: 99%

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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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Regulation of GPCR-mediated smooth muscle contraction: Implications for asthma and pulmonary hypertension

Cited by 39 publications

References 171 publications

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

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

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Regulation of GPCR-mediated smooth muscle contraction: Implications for asthma and pulmonary hypertension

Cited by 39 publications

References 171 publications

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

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

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