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J. Biol. Chem., Vol. 280, Issue 28, 26287-26294, July 15, 2005

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Ryanodine Receptors in Muscarinic Receptor-mediated Bronchoconstriction^*

Wanglei Du, Jonathan A. Stiber, Paul B. Rosenberg, Gerhard Meissner¶, and Jerry P. Eu||

From the Divisions of Pulmonary, Allergy and Critical Care Medicine and Cardiology, Duke University, Medical Center, Durham, North Carolina, 27710 and ^¶Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7260

Ryanodine receptors (RyRs), intracellular calcium release channels essential for skeletal and cardiac muscle contraction, are also expressed in various types of smooth muscle cells. In particular, recent studies have suggested that in airway smooth muscle cells (ASMCs) provoked by spasmogens, stored calcium release by the cardiac isoform of RyR (RyR2) contributes to the calcium response that leads to airway constriction (bronchoconstriction). Here we report that mouse ASMCs also express the skeletal muscle and brain isoforms of RyRs (RyR1 and RyR3, respectively). In these cells, RyR1 is localized to the periphery near the cell membrane, whereas RyR3 is more centrally localized. Moreover, RyR1 and/or RyR3 in mouse airway smooth muscle also appear to mediate bronchoconstriction caused by the muscarinic receptor agonist carbachol. Inhibiting all RyR isoforms with 200 µM ryanodine attenuated the graded carbachol-induced contractile responses of mouse bronchial rings and calcium responses of ASMCs throughout the range of carbachol used (50 nM to 3 µM). In contrast, inhibiting only RyR1 and RyR3 with 25 µM dantrolene attenuated these responses caused by high (>500 nM) but not by low concentrations of carbachol. These data suggest that, as the stimulation of muscarinic receptor in the airway smooth muscle increases, RyR1 and/or RyR3 also mediate the calcium response and thus bronchoconstriction. Our findings provide new insights into the complex calcium signaling in ASMCs and suggest that RyRs are potential therapeutic targets in bronchospastic disorders such as asthma.

Received for publication, March 16, 2005 , and in revised form, May 11, 2005.

^* This work was supported by an American Lung Association Grant RG-191-N and an American Heart Association (Mid-Atlantic Affiliate) grant (to J. P. E.) and National Institutes of Health grants (to P. B. R. and G. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Division of Pulmonary, Allergy and Critical Care Medicine, MSRB 241, Research Dr., Duke University Medical Center, Durham, NC 27710. Tel.: 919-668-3832; Fax: 919-668-0494; E-mail: eu000001{at}duke.edu.

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