Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 293, Issue 6, Pages L1406-L1418Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00312.2007
Keywords
caveolin; G protein-coupled receptor; asthma; histamine; G alpha(q)
Categories
Ask authors/readers for more resources
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 in association with nanospaces involved in Ca2+ homeostasis. Caveolin-1 can modulate localization and activity of signaling proteins, including trimeric G proteins, via a scaffolding domain. We investigated the role of caveolae in contraction and intracellular Ca2+ ([Ca2+](i)) mobilization of ASM induced by the physiological muscarinic receptor agonist, acetylcholine ( ACh). Human and canine ASM tissues and cells predominantly express caveolin-1. Muscarinic M-3 receptors ( M3R) and G alpha(q)/11 cofractionate 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 but not maximum [Ca2+](i) induced by ACh. In contrast, both parameters were reduced for the partial muscarinic agonist, pilocarpine. Fluorescence microscopy revealed that m beta CD disrupted the colocalization of caveolae-1 and M3R, but [N-methyl-H-3] scopolamine 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 peptide mimetic or by small interfering RNA 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 submaximal concentrations of ACh.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available