Asthma is a prevalent disorder associated with airway inflammation and reversible bronchospasm. While the pathophysiology of this disorder is still not well understood, cellular mechanisms that mediate contractile and relaxant responses of airway smooth muscle cells play a pivotal role in the disorder. This proposal seeks to further define the role of membrane potassium channels in the neurohormonal responses of airway smooth muscle, and to determine the specific gene products associated with key aspects of airway smooth muscle function. Substantial experimental evidence indicates that large-conductance calcium-activated potassium channels are important hormone targets, whose open probability is modulated by agents that alter smooth muscle tone and that beta-adrenergic agonists act at least partially by opening these channels. Similarly, delayed-rectifier potassium channels appear to be important involved in defining resting electrical and mechanical excitability. The central hypothesis of the proposal is that potassium channels are key determinants of airway smooth muscle excitability, and that specific potassium channel subtypes subserve discrete physiological functions in airway smooth muscle. The roles of these gene products in determining resting tone and electrical activity and coupling hormone binding to specific cellular events will be determined using electrophysiological and molecular biological approaches. The determination of specific channel/receptor coupling processes, the functional role of specific K channel gene products, an the factors that regulate gene expression should enhance our understanding of the role of potassium channels in normal and abnormal airway smooth muscle.
| Adda, S; Fleischmann, B K; Freedman, B D et al. (1996) Expression and function of voltage-dependent potassium channel genes in human airway smooth muscle. J Biol Chem 271:13239-43 |
