Ion channels regulate cellular responsiveness in both electrically excitablc and """"""""nonexcitable"""""""" cells. Recent evidence has begun to reveal the function of ion channels in signal transduction and other cellular behaviors within the immune system. Corresponding to the diverse roles of ion channels in physiological functions, abnormalities in the activity of ion channels have been implicated in several human diseases. In some cases, these disorders have been shown to involve abnormal regulation of ion channel activity via second messenger systems; in others, the expression of ion channels is altered. The long term goal of this laboratory is to elucidate mechanisms of ion channel gating and selectivity, and to analyze the functional roles of ion channels and their modulation. Through the proposed experiments we hope to define intracellular mechanisms that regulate the activity of ion channels in T lymphocytes. Using techniques of electrophysiology and video-image processing at the level of individual cells, we will investigate an oscillatory Ca2+ signal evoked by mitogens and a regulatory decrease in cell volume induced subsequent to osmotic swelling. Newly defined mitogen-regulated Ca2+ channels appear to underlie the activation of T lymphocytes by antigenic stimulation through a cascade of intracellular events including oscillations in cytosolic [Ca2+]. A different set of channels trigger regulatory changes in cell volume during exposure to hypotonic solutions. Intraccllular mechanisms by which Ca2+, K+, and Cl- ion channels regulate Ca2l- oscillations and volume regulation will be explored through the introduction of second messengers into the cytoplasm. Pharmacological agents will probe the involvement of the four major classes of ion channels during mitogen activation and volume regulation. An ancillary goal in these experiments is to identify potential control points sensitive to new classes of pharmacological agents which may potentially be of therapeutic benefit in the treatment of immunodeficiency, autoimmunity, malignant transformation of lymphoid cells, and cystic fibrosis.
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