Ionic channel regulation by G protein coupled to receptors is a widely-used means of signal transduction. The receptor-G protein-ionic channel pathways are membrane-delimited or direct and cytoplasmic or indirect. Ionic channels form the largest class of G protein membrane effectors and the long-term objective is to delineate the molecular interactions among channel, G protein and receptor. Four hypotheses will be tested in this proposal: 1) that G proteins and ionic channels form complex membrane networks; 2) that other cellular mechanisms compensate for the rate limitations of G protein deactivation; 3) that specificity in these signal pathways is preferential rather than exclusive; and 4) that G protein-ionic channel interactions are direct. Patch clamp and lipid bilayer methods are used to examine the molecular properties of the ionic channels under substrate-controlled conditions. Biochemical methods are used to obtain purified G proteins, channel proteins and specific antibodies. The concentration clamp method is used to supply test agents and to resolve the kinetics of signal flow. Neural and hormonal regulation are essential to proper cardiac function and elucidation of the regulatory mechanisms is fundamental to our understanding of this subject.
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