Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle
"> Figure 1
<p>The intracellular mechanisms of the synergistic effects between β<sub>2</sub>-adrenoceptor agonists and muscarinic receptor antagonists. Not only Ca<sup>2+</sup> sensitization but also Ca<sup>2+</sup> dynamics contributes to the synergistic effect of β<sub>2</sub>-adrenoceptor agonists and muscarinic receptor antagonists (cross talk between β<sub>2</sub>-adrenoceptors and muscarinic receptors). In Ca<sup>2+</sup> dynamic, Ca<sup>2+</sup> influx by VDCE is involved in this phenomenon. VDCE is regulated by membrane potential via K<sub>Ca</sub> channel activity, which is augmented by G<sub>s</sub> coupled to β<sub>2</sub>-adrenoceptor, in contrast, attenuated by G<sub>i</sub> coupled to muscarinic M<sub>2</sub> receptors (dual regulation by G proteins). Increased intracellular Ca<sup>2+</sup> concentration causes contraction by activation of MLCK via Ca<sup>2+</sup>/CAM processes (Ca<sup>2+</sup>-dependent contraction). In Ca<sup>2+</sup> sensitization, PKC is involved in this phenomenon. PKC is activated by muscarinic M<sub>3</sub> receptors. PKC inhibits MP activity via CPI-17 processes. Inactivation of MP causes contraction by increased sensitivity to intracellular Ca<sup>2+</sup> (Ca<sup>2+</sup>-independent contraction). CPI-17 MP is activated by PKC, in contrast, inhibited by PKA. K<sub>Ca</sub> channels and CPI-17 are key molecules for this synergistic effect via the cross talk between these two receptors. This synergism may be caused by Ca<sup>2+</sup> dynamics (tone with changes in concentration of intracellular Ca<sup>2+</sup>) via K<sub>Ca</sub> channel activity reciprocally regulated by G proteins (G<sub>s</sub> and G<sub>i</sub>), and caused by Ca<sup>2+</sup> sensitization (tone without changes in concentration of intracellular Ca<sup>2+</sup>) via CPI-17 reciprocally regulated by protein kinases (PKA and PKC). K<sub>Ca</sub>: large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels. VDCE: voltage-dependent Ca<sup>2+</sup> entry. ACh: acetylcolin, LAMA: long-acting muscarinic receptor antagonist. AC: adenylate cyclase. PKA: protein kinase A. PKC: protein kinase C. CPI-17: C-kinase-potentiated protein phosphatase-1 inhibitor. CaM: calmodulin. MLCK: myosin light chain kinase. MP: myosin phosphatase.</p> "> Figure 2
<p>Involvement of Ca<sup>2+</sup> dynamics and Ca<sup>2+</sup> sensitization in the relaxant effect of β<sub>2</sub>-adrenoceptor agonists. (<b>a</b>,<b>b</b>) Typical samples of continuous recording of tension and F340/F380 demonstrating the inhibitory effect of procaterol (0.1–30 nM) (<b>a</b>) and salbutamol (1–100 nM) (<b>b</b>) on MCh (1 µM)-induced smooth muscle contraction; (<b>c</b>,<b>d</b>) Concentration–response curve for procaterol (0.1–10 nM) (<b>c</b>) and salbutamol (1–100 nM) (<b>d</b>) in tension (□) and F340/F380 (■) in 1 µM MCh-precontracted smooth muscle. Resting state tension and F340/F380 were taken as 0%, and those in each MCh-stimulated state were taken as 100%. MCh, methacholine; PRO, procaterol; SB, salbutamol. **** <span class="html-italic">p</span> < 0.0001; *** <span class="html-italic">p</span> < 0.001; ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 3
<p>Involvement of intracellular Ca<sup>2+</sup> dynamics in the relaxant effect of glycopyrronium. (<b>a</b>) Typical sample of continuous recording of tension and F340/F380 demonstrating the inhibitory effect of glycopyrronium (0.3–10 nM) on MCh (1 µM)-induced contraction; (<b>b</b>) Concentration–response curve for glycopyrronium (0.1–10 nM) in tension (□) and F340/F380 (■) induced by MCh (1 µM). GB, glycopyrronium bromide; MCh, methacholine. ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 4
<p>Effects of combination of procaterol and glycopyrronium on tension and intracellular Ca<sup>2+</sup> concentration induced by muscarinic activation. (<b>a</b>) Typical traces of tension (<b>upper side</b> and F340/F380 (<b>lower side</b>) showing the inhibitory effect of procaterol (1 nM) in the presence of glycopyrronium (3 nM) on MCh (1 µM)-induced contraction; (<b>b</b>–<b>d</b>) Percent inhibition of tension (white columns) and F340/F380 (black columns) in 1 µM MCh-induced contraction under the experimental conditions of 1 nM procaterol (<b>b</b>); 0.1 nM procaterol (<b>c</b>); and 0.3 nM procaterol (<b>d</b>) in the presence of glycopyrronium (3 nM). <b>Left</b>, sum of percent inhibition of tension and F340/F380 by the two agents; <b>Center</b>, BI, expected percent inhibition of tension and F340/F380 calculated by the Bliss independence theory; <b>Right</b>, percent inhibition of tension and F340/F380 with the two agents in combination. PRO, procaterol; GB, glycopyrronium bromide; MCh, methacholine. **** <span class="html-italic">p</span> < 0.0001; *** <span class="html-italic">p</span> < 0.001; ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 5
<p>Effects of salbutamol and glycopyrronium in combination on tension and intracellular Ca<sup>2+</sup> concentration induced by muscarinic activation. (<b>a</b>) Typical sample record of tension (<b>upper side</b>) and F340/F380 (<b>lower side</b>) showing the inhibitory effect of salbutamol (10 nM) in the presence of glycopyrronium (3 nM) against 1 µM MCh-induced contraction; (<b>b</b>,<b>c</b>) Percent inhibition of tension (white columns) and F340/F380 (black columns) in 1 µM MCh-precontracted tissue incubated with 3 nM salbutamol (<b>b</b>) and 10 nM salbutamol (<b>c</b>) in the presence of glycopyrronium (3 nM). <b>Left</b>, sum of percent inhibition of tension and F340/F380 by the two agents; <b>Center</b>, expected percent inhibition of tension and F340/F380 calculated by the Bliss independence theory; <b>Right</b>, percent inhibition of tension and F340/F380 with the two agents in combination. SB, salbutamol; GB, glycopyrronium bromide; MCh, methacholine; BI, Bliss independence. **** <span class="html-italic">p</span> < 0.0001; ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 6
<p>Effects of combination of procaterol and tiotropium on tension and <span class="html-italic">intracellular Ca<sup>2+</sup> concentration</span> induced by muscarinic activation. (<b>a</b>) A typical sample record of tension (<b>upper side</b>) and F340/F380 (<b>lower side</b>) showing the inhibitory effect of procaterol (1 nM) in the presence of tiotropium (1 nM) against 1 µM MCh-induced contraction; (<b>b</b>,<b>c</b>) Percent inhibition of tension (white columns) and F340/F380 (black columns) in 1 µM MCh-precontracted tissue incubated with 1 nM procaterol (<b>b</b>, <span class="html-italic">n</span> = 5) and 0.3 nM procaterol (<b>c</b>, <span class="html-italic">n</span> = 4) in the presence of tiotropium (1 nM). <b>Left</b>, sum of percent inhibition of tension and F340/F380 by the two agents; <b>Center</b>, expected percent inhibition of tension and F340/F380 calculated by the Bliss independence theory; <b>Right</b>, percent inhibition of tension and F340/F380 with the two agents in combination. PRO, procaterol; TIO, tiotropium; MCh, methacholine; BI, Bliss independence. ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 7
<p>Involvement of protein kinase C-induced Ca<sup>2+</sup> sensitization in synergy between β<sub>2</sub>-adrenoceptor agonists and muscarinic receptor antagonists. (<b>a</b>) Typical record of tension (<b>upper side</b>) and F340/F380 (<b>lower side</b>) of the inhibitory effect in combination with procaterol (0.3 nM) and glycopyrronium (3 nM) in the presence of bisindolylmaleimide (10 µM) against 1 µM MCh-induced contraction. In each panel, percent inhibition of tension is represented by white columns, and F340/F380 is represented by black columns; (<b>b</b>) <b>Left</b>, percent inhibition in tension and F340/F380 by bisindolylmaleimide (10 μM); <b>Center</b> , sum of percent inhibition of tension and F340/F380 with bisindolylmaleimide (10 µM) and glycopyrronium (3 nM); <b>Right</b>, percent inhibition of tension and F340/F380 with combination of bisindolylmaleimide (10 µM) and glycopyrronium (3 nM); (<b>c</b>) <b>Left</b>, sum of percent inhibition of tension and F340/F380 with procaterol (0.3 nM) and glycopyrronium (3 nM); <b>Center</b>, percent inhibition of tension and F340/F380 in combination with procaterol (0.3 nM) and glycopyrronium (3 nM); <b>Right</b>, percent inhibition of tension and F340/F380 with combination of procaterol (0.3 nM) and glycopyrronium (3 nM) in the presence of bisindolylmaleimide (10 µM). GB, glycopyrronium bromide; PRO, procaterol; MCh, methacholine; BIS, bisindolylmaleimide. **** <span class="html-italic">p</span> < 0.0001; ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 8
<p>Y-27632-induced Ca<sup>2+</sup> sensitization is not involved in synergy between β<sub>2</sub>-adrenoceptor agonists and muscarinic receptor antagonists. In each panel, percent inhibition of tension is represented by white columns, and F340/F380 is represented by black columns. (<b>a</b>) <b>Left</b>, percent inhibition of tension and F340/F380 with Y-27632 (1 µM); <b>Center</b>, sum of percent inhibition of tension and F340/F380 with Y-27632 (1 µM) and glycopyrronium (3 nM); <b>Right</b>, percent inhibition of tension and F340/F380 with combination of Y-27632 (1 µM) and glycopyrronium (3 nM); (<b>b</b>) <b>Left</b>, sum of percent inhibition of tension and F340/F380 with procaterol (0.3 nM) and glycopyrronium (3 nM); <b>Center</b>, percent inhibition of tension and F340/F380 with combination of procaterol (0.3 nM) and glycopyrronium (3 nM); <b>Right</b>, percent inhibition of tension and F340/F380 with combination of procaterol (0.3 nM) and glycopyrronium (3 nM) in the presence of Y-27632 (1 µM). GB, glycopyrronium bromide; PRO, procaterol; MCh, methacholine. *** <span class="html-italic">p</span> < 0.001; ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 9
<p>Involvement of large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channel in synergy between β<sub>2</sub>-adrenoceptor agonists and muscarinic receptor antagonists. (<b>a</b>) Typical record of tension (<b>upper side</b>) and F340/F380 (<b>lower side</b>) showing the inhibitory effect of a combination of procaterol (1 nM) and glycopyrronium (3 nM) in the presence of iberiotoxin (30 nM) on MCh (1 µM)-induced contraction; (<b>b</b>) Percent inhibition of tension (white column) and F340/F380 (black column) with combination of procaterol (1 nM) and glycopyrronium (3 nM) in the absence (<b>left</b>) or presence (<b>right</b>) of iberiotoxin (30 nM); (<b>c</b>) Percent inhibition of tension (whitecolumn) and F340/F380 (black column) with combination of salbutamol (10 nM) and glycopyrronium (3 nM) in the absence (<b>left</b>) or presence (<b>right</b>) of iberiotoxin (30 nM). IbTX, iberiotoxin; GB, glycopyrronium bromide; PRO, procaterol; SB, salbutamol; MCh, methacholine. **** <span class="html-italic">p</span> < 0.0001; *** <span class="html-italic">p</span> < 0.001; ** <span class="html-italic">p</span> < 0.01; * <span class="html-italic">p</span> < 0.05.</p> "> Figure 10
<p>Clinical effectiveness of Combination of β<sub>2</sub>-adrenoceptor agonists and muscarinic receptor antagonists is in the treatment for COPD via Ca<sup>2+</sup> signaling (Ca<sup>2+</sup> dynamics and Ca<sup>2+</sup> sensitization). Since addition of β<sub>2</sub>-adrenoceptor agonists to muscarinic receptor antagonists markedly enhance an inhibition of airway smooth muscle contraction, combination of these two agents are useful to suppression of excessive stimulation to muscarinic receptors induced by acetylcholine production in the airways, which is an fundamental characteristic for COPD. This phenomenon is due to cross talk between these two receptors via K<sub>Ca</sub> channel-induced Ca<sup>2+</sup> dynamics and PKC-induced Ca<sup>2+</sup> sensitization in airway smooth muscle. Therefore, this combination therapy leads to reducing symptoms such as dyspnea on exertion and frequency of exacerbations, and to improving health status and lung function in patients with COPD.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Inhibitory Effects of Procaterol, Salbutamol, and Glycopyrronium on Tension and Intracellular Ca2+ Concentration in Contracted Muscle
2.2. Effects of Procaterol and Salbutamol Combined with Glycopyrronium on Tension and Intracellular Ca2+ Concentration in Contracted Muscle
2.3. Effects of Procaterol Combined with Tiotropium on Tension and Intracellular Ca2+ Concentration in Contracted Muscle
2.4. Role of Ca2+ Sensitization in the Combined Effects of Procaterol and Glycopyrronium
2.5. Role of Large-Conductance Ca2+-Activated K+ Channels in Ca2+ Dynamics due to Procaterol and Salbutamol with Glycopyrronium
3. Discussion
4. Experimental Section
4.1. Tissue Preparation and Bathing Solution
4.2. Isometric Tension Recording and Measurement of Fura-2 Fluorescence
4.3. Experimental Protocol
4.4. Analysis of Synergistic Effect
4.5. Materials
4.6. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Fukunaga, K.; Kume, H.; Oguma, T.; Shigemori, W.; Tohda, Y.; Ogawa, E.; Nakano, Y. Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle. Int. J. Mol. Sci. 2016, 17, 1590. https://doi.org/10.3390/ijms17091590
Fukunaga K, Kume H, Oguma T, Shigemori W, Tohda Y, Ogawa E, Nakano Y. Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle. International Journal of Molecular Sciences. 2016; 17(9):1590. https://doi.org/10.3390/ijms17091590
Chicago/Turabian StyleFukunaga, Kentaro, Hiroaki Kume, Tetsuya Oguma, Wataru Shigemori, Yuji Tohda, Emiko Ogawa, and Yasutaka Nakano. 2016. "Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle" International Journal of Molecular Sciences 17, no. 9: 1590. https://doi.org/10.3390/ijms17091590