The long-term objectives are to molecularly characterize potassium channels and to understand their functional roles in the mammalian brain. Specifically, the plan over the next five years is (1) to study the function and regulation of the Kv1.4 voltage-gated [potassium channels prevent in the axons and nerve terminals of many central neurons, (2) to study the possible role of a G protein-activated potassium channel as an effector that mediates the action of a wide range of neurotransmitter including serotonin, acetylcholine and GABA, and (3) to test the possibility that neuronal excitability is regulated by the energy level of the neuron partly via inhibition of a potassium channel by ATP. In addition to contributing to our understanding of the basic mechanisms underlying the function and plasticity of the mammalian brain, these studies may be relevant to current efforts tin the development of drugs that affect potassium channel function, used for treatment of diseases such as diabetes, arrhythmia, multiple sclerosis, or incontinence. Better understanding of the function and molecular diversity of potassium channels in the mammalian brain may also improve the likelihood of developing regimen to minimize neuronal damage due to ischemia or anoxia or treatments for behavioral disorders. One such disorder, episodic ataxia, has been found to arise from mutations of the Kv1.1 voltage-gated potassium channel. The research design is to first clone potassium channel genes that are expressed in the mammalian brain, and then study these potassium channels using two complimentary approaches. First, expression of cloned potassium channels in cell lines or Xenopus oocytes makes it possible to carry out mechanistic studies on the assembly, function and regulation of individual channel types. Second, expression of wildtype or mutated potassium channels in transgenic mice or removal of the endogenous potassium channels in transgenic mice or removal of the endogenous potassium channel gene function via homologous recombination will be carried out to analyze the function of these potassium channels at the level of central neuronal signaling and behavior.
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