PI: Spitzer IBN: 9603978 Dr. Spitzer will analyze the molecular mechanisms that underlie expression of potassium current in embryonic spinal nerve cell. Nerve cells transmit information with electrical signals, and acquire the ability to generate these signals called action potentials at very early stages of differentiation. Initially, these action potentials allow the entry of substantial amounts of calcium ions. Dr. Spitzer has shown that this calcium influx generates important signals that regulate several aspects of the development of nerve cells. However, since this amount of calcium entry is toxic to mature nerve cells, the neurons must dramatically reduce the amount of calcium entry as they mature. In earlier work Dr. Spitzer showed that the reduction of calcium influx is the result of an increase in potassium current that flows out of the nerve cells through protein pores, called potassium channels, opposing the calcium influx. In the work supported by this grant he will determine the basis of the developmental increase in this potassium current. Preliminary results suggest that expression of a particular gene, known as Kv2.2, which encodes the protein of which potassium channels are composed, may be responsible for the increase in this potassium current. Dr. Spitzer will use antisense DNA sequences to suppress the synthesis of the protein in nerve cells isolated and growing in culture. He will take advantage of the availability of a toxin, hanatoxin, that is a specific blocker of these channels, to check the success of these experiments. If the antisense treatment suppresses expression of the Kv2.2 protein, the toxin will no longer affect the potassium current. The results from the project will provide new knowledge about the regulation of excitability in the spinal cord. The fact that the central nervous system of young vertebrates is especially vulnerable to epileptic seizure activity may be partly due to the calcium influx that is part of the early signaling mac hinery. In the future it may be possible to suppress this calcium influx selectively by regulating the expression of particular potassium channel genes.
