This Center application is being submitted in response to the National Institute of Mental Health's Program Announcement """"""""Centers for Neuroscience Research"""""""". The Caltech Center for Neuroscience Research brings together eight research groups in cellular and molecular neuroscience. A large number of proteins that mediate specialized communication within and among neurons have recently been discovered. Key questions now include the following: What is the significance of the large variety of isozymes of closely related neurotransmitter and neurohormone receptors? How do the small variations in structure of these molecules influence signal transduction? How are the networks of intracellular regulatory pathways that process receptor signals organized within different kinds of neurons? How do variations in concentration and spatial arrangement of key regulatory molecules, such as G proteins, protein kinases and protein phosphatases, influence patterns of electrical activity and other major signaling properties of different neuronal types? How is transmitter release controlled at the molecular level in different classes of neurons? Are there variations in the release machinery that produce major differences in mechanisms of regulation of transmitter release? To what extent do intracellular signaling pathways important in neuronal function overlap with those important for development? And finally, what new signaling pathways remain to be discovered? The central hypotheses emphasize both unity and diversity. It is suggested (1) that most classes of signaling protein -- 7-helix receptors, G proteins, enzyme effectors, kinases, ligand-gated channels, voltage-gated channels, transporters, and others now being discovered -- participate in several distinct types of signaling pathways within neurons; and (2) that the complexity and diversity of molecular and cellular signaling pathways accounts for much of the functional diversity of CNS neurons. The range of favorable preparations constitutes a strength of the Center and includes: rat CNS neurons in slices, organotypic cultures, and dissociated cultures; rat olfactory epithelium; neuronal cell lines; insect central nervous systems; Xenopus oocytes expressing signaling proteins; Xenopus brains; non-neuronal cells modified to function as artificial neurons; and bacteria expressing G proteins. The technical approaches are highly appropriate and promise rapid progress: nucleic acid molecular biology; antisense suppression; heterologous expression in mammalian cells and oocytes; protein chemistry; electrophysiology; immunocytochemistry; optical recording and imaging; numerical simulation and analysis; and bacterial genetics. Research on the cellular and molecular basis of neuronal function is relevant to several neurological diseases, to mental disease, and to substance abuse.
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