ION CHANNELS IN LYMPHOCYTES--GENETIC PROBES

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Potassium (K) channels control a wide array of physiological processes, including regulation of membrane potential and cell volume in diverse tissues, and modulation of electrical excitability in the nervous system. Our studies have revealed three distinct types of K channels in T lymphocytes (n, n' and l) that play a role in mitogen-activation and differentiation. Expression of these channels is dependent on the phenotype and on the activation and differentiation status of T cells. We have also identified a link between altered K channel expression in T lymphocytes and four disparate autoimmune disorders: systemic lupus erythematosus, type-1 diabetes mellitus, rheumatoid arthritis and multiple sclerosis. Using molecular techniques we have characterized the genes encoding the types n and l K channels in T cells; the human chromosomal locations of 14 related K channel genes have been determined. Anti-peptide antibodies against the T cell K channel proteins have allowed us to start measuring the rate of turnover of channel proteins in T cells. In this proposal we plan to extend our studies to further define the role of K channels in T cell activation and differentiation. The overall goal of the proposed experiments is three-fold. First, we will map the transcripts encoding T cell K channels, and identify tissue-specific and activation-dependent regulatory elements. Second, we will measure the rate of synthesis and degradation of the T cell K channel transcripts during T and B cell activation and development. Third, using anti-peptide antibodies we will study channel protein turnover in lymphoid cells. Comparison of normal and diseased T cells may reveal abnormalities In channel-gene or protein regulation associated with autoimmunity. In the course of these studies we may reveal DNA binding proteins that modulate K channel-gene activity during T cell proliferation.