Abstract

Anesthetic relaxation of bronchial smooth muscle is in part mediated by decreasing Ca sensitivity of the myocyte (force produced per Cai). The experiments in this proposal focus on the mechanisms involved. The investigators have found that volatile anesthetics decrease phosphorylation of the regulatory myosin light chain during stimulation of bronchial smooth muscle by membrane receptor agonists.
The first aim explores anesthetic mechanisms responsible for reduction in rMLC phosphorylation. The effects of anesthetics on G-protein regulation of myosin light chain phosphatase will be focus of this aim. Since there is evidence that Ca sensitivity may also be regulated in airway smooth muscle independent of rMLC phosphorylation (possibly involving tyrosine kinases), the second aim will investigate how anesthetics affect tyrosine phosphorylation of mitogen-activated protein kinases and consequent changes in caldesmon phosphorylation. These experiments will utilize both B escin permeabilized canine tracheal and human bronchial smooth muscle preparations. In these preparations, calcium levels can be controlled, and membrane receptor second messenger systems that alter calcium sensitivity are intact.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045532-12
Application #
6389152
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Croxton, Thomas
Project Start
1990-07-01
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
12
Fiscal Year
2001
Total Cost
$261,415
Indirect Cost

  Institution

Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905

  Publications

Streiff, John H; Jones, Keith A (2008) Volatile anesthetic binding to proteins is influenced by solvent and aliphatic residues. J Chem Inf Model 48:2066-73
Nakayama, Tetsuzo; Penheiter, Alan R; Penheiter, Sumedha G et al. (2006) Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein. Anesthesiology 105:313-24
Hayashi, Masao; Penheiter, Sumedha G; Nakayama, Tetsuzo et al. (2006) Halothane does not inhibit the functional coupling between the beta2-adrenergic receptor and the Galphas heterotrimeric G protein. Anesthesiology 104:754-62
Streiff, John H; Allen, Thomas W; Atanasova, Elena et al. (2006) Prediction of volatile anesthetic binding sites in proteins. Biophys J 91:3405-14
Taniguchi, Miwa; Kwak, Young Lan; Jones, Keith A et al. (2006) Nitric oxide sensitivity in pulmonary artery and airway smooth muscle: a possible role for cGMP responsiveness. Am J Physiol Lung Cell Mol Physiol 290:L1018-27
Jin, Fang; Wang, Shuyan; Spencer, Joshua D et al. (2005) Effect of halothane on galphai-3 and its coupling to the M2 muscarinic receptor. Anesthesiology 103:1015-25
Nakayama, Tetsuzo; Hayashi, Masao; Warner, David O et al. (2005) Anesthetics inhibit membrane receptor coupling to the Gq/11 heterotrimeric G protein in airway smooth muscle. Anesthesiology 103:296-305
Streiff, John; Warner, David O; Klimtchuk, Elena et al. (2004) The effects of hexanol on Galpha(i) subunits of heterotrimeric G proteins. Anesth Analg 98:660-7, table of contents
Sakihara, Chie; Perkins, William J; Warner, David O et al. (2004) Anesthetics inhibit acetylcholine-promoted guanine nucleotide exchange of heterotrimeric G proteins of airway smooth muscle. Anesthesiology 101:120-6
Streiff, John H; Juranic, Nenad O; Macura, Slobodan I et al. (2004) Saturation transfer difference nuclear magnetic resonance spectroscopy as a method for screening proteins for anesthetic binding. Mol Pharmacol 66:929-35

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