The long term objective of this research is to learn about synaptic transmission by the study of synaptic receptors. A large number of medical problems, including epilepsy, mental illness, and drug addiction and abuse, ultimately may be based in some form of synaptic disfunction at the cellular level. Furthermore, normal development and learning also are thought to involve synaptic function at the cellular level. Synaptic receptors are essential, and very well defined, molecular components of all chemical synapses. By using patch clamp techniques one can evaluate the function of synaptic receptors in several precise ways. The information obtained can then be used to analyze and interpret studies of synaptic transmission mediated by particular receptors. In the present project it is proposed to study a particular serotonin receptor referred to as the 5-HT 3 receptor. With the recent classification of this receptor in peripheral tissue, and its discovery in mammalian brain and clonal cell lines, one can study the receptor in clonal cell lines, and obtain very detailed information about its basic mechanism of activation, desensitization, plasticity, and pharmacology. The 5-HT 3 receptor is unique among serotonin receptors in that it responds to agonists with a rapid and vigorous excitation. This proposal presents a variety of experiments to characterize this receptor. The kinetics of activation and desensitization will be examined with rapid iontophoretic techniques. The basic channel properties will be studied with noise analysis and single channel techniques. We have found that the desensitization of the 5-HT 3 receptor can be modulated in more than one way with a variety of different treatments. Desensitization modulation is an important new paradigm for synaptic plasticity. The modulation of receptor desensitization will be studied to try to determine cellular mechanisms, and to try to determine what receptors can be activated to produce this behavior. It is anticipated that these studies will provide insights not only into specific physiological systems that employ the 5-HT 3 receptor, but into more general aspects of synaptic receptors as well.
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