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Int. J. Mol. Sci. 2018, 19(7), 1999; https://doi.org/10.3390/ijms19071999

Involvement of Allosteric Effect and KCa Channels in Crosstalk between β2-Adrenergic and Muscarinic M2 Receptors in Airway Smooth Muscle

1
Department of Respiratory Medicine and Allergology, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama 589-8511, Japan
2
Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
*
Author to whom correspondence should be addressed.
Received: 23 March 2018 / Revised: 24 June 2018 / Accepted: 4 July 2018 / Published: 9 July 2018
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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Abstract

To advance the development of bronchodilators for asthma and chronic obstructive pulmonary disease (COPD), this study was designed to investigate the mechanism of functional antagonism between β2-adrenergic and muscarinic M2 receptors, focusing on allosteric effects and G proteins/ion channels coupling. Muscarinic receptor antagonists (tiotropium, glycopyrronium, atropine) synergistically enhanced the relaxant effects of β2-adrenergic receptor agonists (procaterol, salbutamol, formoterol) in guinea pig trachealis. This crosstalk was inhibited by iberitoxin, a large-conductance Ca2+-activated K+ (KCa) channel inhibitor, whereas it was increased by verapamil, a L-type voltage-dependent Ca2+ (VDC) channel inhibitor; additionally, it was enhanced after tissues were incubated with pertussis or cholera toxin. This synergism converges in the G proteins (Gi, Gs)/KCa channel/VDC channel linkages. Muscarinic receptor antagonists competitively suppressed, whereas, β2-adrenergic receptor agonists noncompetitively suppressed muscarinic contraction. In concentration-inhibition curves for β2-adrenergic receptor agonists with muscarinic receptor antagonists, EC50 was markedly decreased, and maximal inhibition was markedly increased. Hence, muscarinic receptor antagonists do not bind to allosteric sites on muscarinic receptors. β2-Adrenergic receptor agonists bind to allosteric sites on these receptors; their intrinsic efficacy is attenuated by allosteric modulation (partial agonism). Muscarinic receptor antagonists enhance affinity and efficacy of β2-adrenergic action via allosteric sites in β2-adrenergic receptors (synergism). In conclusion, KCa channels and allosterism may be novel targets of bronchodilator therapy for diseases such as asthma and COPD. View Full-Text
Keywords: synergistic effects; G protein; large-conductance Ca2+-activated K+ channels; L-type voltage-dependent Ca2+ channels; β2-adrenoceptor agonists; muscarinic receptor antagonists; asthma; COPD synergistic effects; G protein; large-conductance Ca2+-activated K+ channels; L-type voltage-dependent Ca2+ channels; β2-adrenoceptor agonists; muscarinic receptor antagonists; asthma; COPD
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kume, H.; Nishiyama, O.; Isoya, T.; Higashimoto, Y.; Tohda, Y.; Noda, Y. Involvement of Allosteric Effect and KCa Channels in Crosstalk between β2-Adrenergic and Muscarinic M2 Receptors in Airway Smooth Muscle. Int. J. Mol. Sci. 2018, 19, 1999.

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