We are studying the molecular structure and function of synaptic connections between neurons in the central nervous system. Derangements in the regulation of these connections are an important part of the pathology of several neurological and mental diseases including epilepsy, Alzheimer's disease, schizophrenia, and depression. Many neurotransmitters and neurohormones regulate synaptic function by altering intracellular levels of calcium ion. We are studying the mechanisms by which these fluctuations in calcium levels alter synaptic function. We will focus on the study of a synaptic regulatory pathway that has as its central element an abundant, brain-specific calcium and calmodulin-dependent protein kinase. This kinase is a large oligomer of two distinct but homologous catalytic subunits called alpha and beta. In the forebrain, including the hippocampus, cortex and striatum, the kinase is extremely abundant (1% of total protein) and is composed mainly of alpha subunits. It is a major component of synapses and is concentrated in a cytoskeletal structure called the postsynaptic density. When activated by a brief rise in calcium concentration, the kinase phosphorylates itself and then remains active to phosphorylate other proteins even after the calcium concentration falls. We will test the hypothesis that this is a mechanism by which long-lasting changes in synaptic function are generated following brief bursts of synaptic activity. We will determine the structure of the autophosphorylation sites by recombinant DNA and biochemical methods, then characterize the brain phosphatases responsible for dephosphorylation of each of these sites. We will raise antibodies that specifically recognize the autophosphorylated sites on the kinase and others that recognize the phosphorylated form of kinase substrates. We will use these to study, with high spatial and temporal resolution, the physiological circumstances under which the kinase is activated and specific substrates become phosphorylated. We will continue a study of the association of the kinase with the cytoskeleton by biochemical and recombinant DNA techniques. Our goal in the next few years is to clarify the possible regulatory functions of this calcium-dependent protein kinase system. Our long-term goal is to correlate information about this pathway with similar information about other calcium regulated pathways in order to understand the concerted responses to changing calcium levels in CNS neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS017660-07
Application #
3397703
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1981-07-01
Project End
1992-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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Zhou, Yu; Takahashi, Eiki; Li, Weidong et al. (2007) Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. J Neurosci 27:13843-53
Ouyang, Yannan; Wong, Michael; Capani, Francisco et al. (2005) Transient decrease in F-actin may be necessary for translocation of proteins into dendritic spines. Eur J Neurosci 22:2995-3005
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Oh, Jeong S; Manzerra, Pasquale; Kennedy, Mary B (2004) Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 279:17980-8
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Kennedy, M B (2000) Signal-processing machines at the postsynaptic density. Science 290:750-4

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