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Am J Physiol Lung Cell Mol Physiol (September 21, 2007). doi:10.1152/ajplung.00312.2007
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Submitted on August 4, 2007
Accepted on September 20, 2007

Caveolae Facilitate Muscarinic Receptor Mediated Intracellular Ca2+ Mobilization and Contraction in Airway Smooth Muscle

Reinoud Gosens1, Gerald L. Stelmack2, Gordon Dueck3, Mark M. Mutawe2, Martha A Hinton2, Karol D. McNeill2, Angela Paulson3, Shyamala Dakshinamurti4, William T Gerthoffer5, James A Thliveris6, Helmut Unruh7, Johan Zaagsma8, and Andrew John Halayko9*

1 Physiology, University of Manitoba, Winnipeg, Canada; Molecular Pharmacology, University of Groningen, Groningen, groningen, Netherlands; Internal Medicine, University of Manitoba, Winnipeg, Canada; Section of Respiratory Disease, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada; CIHR National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, Canada
2 Physiology, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada
3 Physiology, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada; CIHR National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, Canada
4 Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada; Physiology, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada
5 Pharmacology, University of Nevada, Reno, Nevada, United States
6 Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada
7 Section of Thoracic Surgery, University of Manitoba, Winnipeg, Canada
8 Molecular Pharmacology, University of Groningen, Groningen, groningen, Netherlands
9 Physiology, University of Manitoba, Winnipeg, Canada; Internal Medicine, University of Manitoba, Winnipeg, Canada; Section of Respiratory Disease, University of Manitoba, Winnipeg, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada; CIHR National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, Canada; Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada

* To whom correspondence should be addressed. E-mail: ahalayk{at}cc.umanitoba.ca.

Contractile responses of airway smooth muscle (ASM) determine airway resistance in health and disease. Caveolae microdomains in the plasma membrane are marked by caveolin proteins, and are abundant in contractile smooth muscle associated with nanospaces involved in Ca2+ homeostasis. Via a scaffolding domain, caveolin-1 modulates localization and activity of signaling proteins, including trimeric G-proteins. We investigated the role of caveolae in contraction and intracellular Ca2+ ([Ca2+]i) mobilization of ASM in response to the muscarinic receptor agonist, acetylcholine (ACh). Human and canine ASM tissues and cells predominantly express caveolin-1. Muscarinic M3 receptors (M3R) and G{alpha}q/11 co-fractionate with caveolin-1-rich membranes of ASM tissue. Caveolae disruption with {beta}-cyclodextrin in canine tracheal strips reduced sensitivity, but not maximum isometric force induced by ACh. In fura-2 loaded canine and human ASM cells, exposure to methyl-{beta}-cyclodextrin (m{beta}CD) reduced sensitivity to, but not maximum [Ca2+]i induced by ACh, but both parameters were reduced for the partial muscarinic agonist, pilocarpine. Fluorescence microscopy revealed that m{beta}CD disrupted the co-localization of caveolae-1 and M3R, but H3-N-methyl-scapolamine receptor binding assay revealed no effect on muscarinic receptor availability or affinity. To dissect the role of caveolin-1 in ACh induced [Ca2+]i flux, we disrupted its binding to signaling proteins using either a cell permeable caveolin-1 scaffolding domain (CSD) peptide mimetic or by siRNA knockdown. Similar to the effects of m{beta}CD, direct targeting of caveolin-1 reduced sensitivity to ACh but maximum [Ca2+]i mobilization was unaffected. These results indicate caveolae and caveolin-1 facilitate [Ca2+]i mobilization leading to ASM contraction induced by sub-maximal concentrations of ACh.




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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
P. Sharma, T. Tran, G. L. Stelmack, K. McNeill, R. Gosens, M. M. Mutawe, H. Unruh, W. T. Gerthoffer, and A. J. Halayko
Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation
Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L57 - L68.
[Abstract] [Full Text] [PDF]


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