The long-term goal of the studies in this application is to understand the relationship between ion channel activity and the initiation and regulation of smooth muscle contraction. At the center of this relationship is the effect of ion channel activity on the levels of internal Ca2+ which, in turn, affects the contractile state of the cell. Since smooth muscle plays a key role in such important health related areas as the control of blood pressure, gastrointestinal motility, tissue perfusion, etc., an understanding of this relationship will lay the groundwork for understanding the normal and diseases states and should help point the way to new therapeutic interventions. Specifically, the proposed studies have three immediate goals: (1) to understand the role of stretch-activated cation channels in the myogenic component of stretch-induced contraction through their effect on internal Ca2+, (2) to understand the role of cation channels activated by caffeine in the regulation of internal Ca2+, and (3) to understand the role of neuro- transmitters and internal Ca2+ in the generation and regulation of ion channel activity underlying spontaneous transient outward currents which can, in turn, affect the contractile state of the cell. A common theme throughout these studies is the dual relationship between intracellular Ca2+ and ion channel activity. Thus, ion channel activity affects the internal Ca2+ concentration by admitting Ca2+ into the cell and the change in internal Ca2+ can, in turn, affect the activity of ion channels. The methodology mostly involves patch-clamp techniques for recording whole-cell and single channel currents often coupled with simultaneous digital imaging microscopy of intracellular Ca2+.
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