THE MOLECULAR BASIS OF MEMBRANE EXCITABILITY

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The goal of the proposed research is to understand the electrical signals of nerve and heart in terms of the function and regulation of ionic channels. Voltage clamp techniques are used to measure the current through these channels in response to electrical and chemical stimuli. The modulation of the function of sodium and calcium channels by neurotransmitters and hormones will be investigated in primary cultures of dissociated neuronal and cardiac cells. In this laboratory, beta-adrenergic stimulation has been found to substantially increase the conductance of at least one type of sodium channel found in a vertebrate sensory neuron. This finding is especially significant since the voltage-gated sodium channel plays an essential role in the initiation and propagation of the cellular electrical signals of nerve, muscle and cardiac cells. Thus, because the sodium channel is responsible for the rising phase of the action potential, hormonal or neurotransmitter modulation of sodium channel function may play a fundamental role in modulating cellular electrical activity. The whole-cell voltage clamp technique will be used to investigate the ionic channel mechanisms underlying the increase in sodium current. In addition, voltage clamp measurements combined with pharmocological and biochemical techniques will be used to probe the cellular mechanisms mediating the response. Experiments will be carried out to determine the generality of this humoral modulation of sodium channels, by determining: 1) the extent to which this modulation occurs in other cell types of the same species; and 2) the extent to which this modulation occurs in other species of animals. The modulation of calcium channels by adenosine will be studied in cultured neurons and heart cells. Electrical and biochemical techniques will be applied to probe the cellular mechanisms mediating this regulatory response. Understanding the dynamic regulation of sodium and calcium channel function is essential to an understanding of the complex electrical activity of healthy neurons and heart cells. It will also be important to the understanding of altered function in neural or cardiac disease, and should aid in the development of pharmacological strategies for therapeutic intervention in disease of excitable tissues.