The objectives of this proposal are to determine the molecular processes underlying spontaneous Ca2+ release events in smooth muscle cells. Spontaneous and triggered release of Ca2+ ions from the sarcoplasmic reticulum of smooth muscle cells is a key event associated with contraction of the smooth muscle and bronchoconstriction of the airways. In recent years it has become clear that this Ca2+ release process is quite complicated, with two major intracellular Ca2+ release. Ryanodine receptors comprise one family of Ca2+ release channels; the function of these channels in skeletal and cardiac muscle is well established, but their role in the contraction of smooth muscle is less clear. A prominent feature of the electrical activity of smooth muscle cells in the airways is the appearance of spontaneous depolarizing and spontaneous hyperpolarizing currents. These currents arise from the opening of calcium-sensitive membrane channels following a brief release of calcium from the sarcoplasmic reticulum. This calcium release has been shown to arise from the spontaneous gating of ryanodine receptors, and the Ca2+ release that occurs have been termed Ca2+ sparks. These sparks arise from specific areas within smooth muscle cells, analogous to their appearance at the triads of striated muscle. Release of Ca2+ is also propagated as waves throughout the cell cytoplasm by the gating of ryanodine receptors. The underlying structures and channels mediating and regulating spontaneous Ca2+ release and propagated Ca2+ waves will be determined in this proposal. Mice have been generated lacking specific elements of ryanodine receptor complex and the properties of the Ca2+ release in myocytes from these cells will be determined as a way of identifying the specific role of individual proteins in this complex process. Moreover, the effect of this deletion on airway function will be determined, in order to assess the importance of this process in the complex control of airway tone.
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