CA2+/CALMODULIN-KINASE II--BRAIN SUBSTRATES

  • Soderling, Thomas, (PI)

    Project: Research project

    Description

    The objective of these studies is to identify physiological
    functions of Ca++/ Calmodulin-dependent protein kinase II (CaM-
    kinase II) in neural tissues. CaM-kinase II is of particular
    interest in this context since 1) it constitutes about 1% of brain
    protein, 2) it constitutes about 50% of the postsynaptic density
    (PSD) protein, and 3) it undergoes a unique autophosphorylation
    that converts it to a Ca++ -independent form. Our studies will
    utilize a combination of biochemical and electrophysiological
    approaches to investigate physiological functions of the cytosolic
    and membrane-associated brain CaM-kinase II. Potential targets of cytosolic CaM-kinase II that will be
    investigated include tyrosine hydroxylase, the rate-limiting enzyme
    in catecholamine and several other regulatory CaM-binding proteins.
    With reference to tyrosine hydroxylase, our goals will be to
    establish its in vivo phosphorylation by CaM-kinase II and the
    regulatory role of an activator protein that is specific for
    tyrosine hydroxylase that has been phosphorylated by CaM-kinase
    II. These studies will utilize pinocytotic introduction of
    antibodies against CaM-kinase II or the activator protein into PC12
    cells. A number of known CaM-binding proteins will be screened for
    specific phosphorylation by the Ca -independent form of CaM-kinase
    II. We are especially interested in regulatory phosphorylation
    sites which are blocked when Ca /CaM is bound to the CaM-binding
    proteins. A major focus of these studies will be the CaM-kinase II localized
    in the PSD. Of special interest is the potential role of this
    kinase in regulating certain ion channels, specifically, the NMDA-
    receptor/ion channel and the dihydropyridine-sensitive Ca channel.
    These studies will combine radioligand binding analyses and patch-
    clamp studies. We are particularly interested in potential
    regulation of these ion channels by protein phosphorylation and by
    GTP-binding proteins. The NMDA channel is of special relevance due
    to its likely involvement in synaptic plasticity such as long-term
    potentiation and kindling, and perhaps in epilepsy.
    StatusFinished
    Effective start/end date4/1/894/30/12

    Funding

    • National Institutes of Health
    • National Institutes of Health: $340,042.00
    • National Institutes of Health: $273,512.00
    • National Institutes of Health: $336,875.00
    • National Institutes of Health
    • National Institutes of Health: $330,138.00
    • National Institutes of Health: $262,992.00
    • National Institutes of Health
    • National Institutes of Health: $358,625.00
    • National Institutes of Health: $358,625.00
    • National Institutes of Health: $336,875.00
    • National Institutes of Health
    • National Institutes of Health: $346,779.00
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health: $333,507.00
    • National Institutes of Health: $252,881.00
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health
    • National Institutes of Health: $350,198.00
    • National Institutes of Health

    Fingerprint

    Calcium-Calmodulin-Dependent Protein Kinase Type 2
    Calcium-Calmodulin-Dependent Protein Kinases
    Neuronal Plasticity
    Glutamate Receptors
    alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
    Phosphorylation
    Ion Channels
    Synapses
    Organized Financing
    Long-Term Potentiation
    Calcineurin
    Neurons
    Phosphoprotein Phosphatases
    Neurotransmitter Agents
    Brain
    Learning
    Synaptic Transmission
    Phosphotransferases
    Efficiency
    Proteins

    ASJC

    • Medicine(all)
    • Neuroscience(all)