Ion channels in lymphocytes subserve a variety of functions, including the rise in intracellular calcium induced by antigen binding to the T cell receptor, and lymphokine secretion and proliferation. Manyof these functions are in turn modulated by endogenous and exogenous substances, such as catecholamines, steroids, neurotransmitters, and nicotine and drugs of abuse, as well as by disease states. Much recent evidence has accumulated to suggested the hypothesis that immunomodulating substances or diseases may induce or inhibit particular immune functions by altering the properties of lymphocyte membrance channels. It is the major goal of this proposal to elucidate the cellular and molecular mechanisms by which lymphocyte channels initate, determine and regulate the immune response. Using fluorescence and patch clamp recording techniques we will study the properties and regulation of three lymphocyte ion channels in a human lymphoblastoid cell line, the n type voltage dependent potassium channel K (V), the calcium dependent potassium channel K (Ca) and the calcium release-activated calcium channel (CRAC). The properties of these channels will be studied under the effects of certain steroid hormones, progesterone and estradiol, and novel marine cembranoids, which are diterpenoid toxins derived from Caribbean soft corals (gorgonians). The steroids and toxins will be examined for their effects on intracellular calcium mobilization and activation and inactivationkinetics in both the K (V) and K (Ca) channels, and for effects on Icrac (current through CRAC channels). The information obtained on T lymphocyte channel properties and their regulationwillb e very useful for the design of novel therapeutic agents, mainly targeted at these membrane ionic channels. The work proposed here will add to our information on the regulation of T cell channels and their immunomodulatory function, and will help further our understanding of the immune response and how to manage it successfully in states of immunodeficiency, autoimmunity, inflammation, and other disorders.
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