and specific aims): Contraction of airway smooth muscle causes airway obstruction and relaxation of this muscle is the principal action of beta-adrenergic agonists used to treat asthma. Calcium ion is an important second messenger that contributes to the determination of tension in smooth muscle. The application hypothesizes that the cytosol is not homogeneous with respect to calcium concentrations. There are calcium influx pathways into the cell that are not major determinants of (Ca2+)i and, therefore, not major determinants of tension. Both beta-adrenergic and muscarinic agonists stimulate calcium influx at the cell periphery in order to maintain sarcoplasmic reticulum (SR) calcium stores, but the two different agonists have opposite effects on (Ca2+)i.
The specific aims are to 1) determine how beta-adrenergic agonists decrease (Ca2+)i; 2) determine whether beta-adrenergic agonists stimulate calcium influx pathways that have minimal effects on (Ca2+)i because of SR uptake refilling processes; 3) during muscarinic stimulation, determine whether the calcium content of the SR regulates calcium influx; 4) during sustained muscarinic stimulation, determine whether calcium influx occurs via multiple pathways, one of which is a minor determinant of (Ca2+)i because of SR uptake and refilling processes; and 5) characterize the detection of calcium at the cell periphery using specific fura-2 AM loading conditions.
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