Excitatory neurotransmission in the central nervous system is mediated largely by the neurotransmitter glutamate acting on specific glutamate receptors. It is well known that the efficiency of transmission at these glutamatergic synapses can be decreased (long-term depression) or enhanced (long-term potentiation) for prolonged periods of time. This synaptic plasticity is due to both alterations in the release of neurotransmitter (presynaptic mechanism) and in the responsiveness of the postsynaptic neuron. This grant application will investigate several Ca2+ dependent mechanisms that may account for postsynaptic changes in glutamate receptor ion channels (GluRs). Results from our laboratory, as well as from several other research groups, has provided strong evidence that a key player in these postsynaptic Ca2+ dependent changes is phosphorylation of glutamate receptor ion channels (GluRs) by Ca2+/calmodulin-dependent protein kinase II (CaM-K II) and perhaps dephosphorylation by calcineurin. This grant application will investigate regulatory functions of CaM-K II and calcineurin on all three types of GluRs.
The specific aims are: l. Investigate the phosphorylation and regulation of AMPA-type GluRs by CaM-K II and protein phosphatases. 2. Investigate the regulation of kainate-type GluRs by CaM-K II. 3. Determine the roles of protein kinases and phosphatases in two Ca2+ dependent modulations of NMDA-type GluRs. These studies will include both biochemical, molecular biological and electrophysiological techniques using cultured hippocampal neurons and the various GluRs expressed in HEK 293 cells. The results of these studies have strong implications for modulating synaptic efficiency in paradigms of learning and memory and for neuronal excitability in epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027037-10
Application #
2873148
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Jacobs, Margaret
Project Start
1989-04-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Chen, Yishen; Derkach, Victor A; Smith, Peter A (2016) Loss of Ca(2+)-permeable AMPA receptors in synapses of tonic firing substantia gelatinosa neurons in the chronic constriction injury model of neuropathic pain. Exp Neurol 279:168-177
Fortin, Dale A; Srivastava, Taasin; Dwarakanath, Diya et al. (2012) Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors. J Neurosci 32:8127-37
Fortin, Dale A; Srivastava, Taasin; Soderling, Thomas R (2012) Structural modulation of dendritic spines during synaptic plasticity. Neuroscientist 18:326-41
Srivastava, Taasin; Fortin, Dale A; Nygaard, Sean et al. (2012) Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII. J Neurosci 32:5620-30
Wayman, Gary A; Tokumitsu, Hiroshi; Davare, Monika A et al. (2011) Analysis of CaM-kinase signaling in cells. Cell Calcium 50:1-8
Saneyoshi, Takeo; Fortin, Dale A; Soderling, Thomas R (2010) Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways. Curr Opin Neurobiol 20:108-15
Fortin, Dale A; Davare, Monika A; Srivastava, Taasin et al. (2010) Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I. J Neurosci 30:11565-75
Santos, Sonia F A; Luz, Liliana L; Szucs, Peter et al. (2009) Transmission efficacy and plasticity in glutamatergic synapses formed by excitatory interneurons of the substantia gelatinosa in the rat spinal cord. PLoS One 4:e8047
Pinto, Vitor; Szucs, Peter; Derkach, Victor A et al. (2008) Monosynaptic convergence of C- and Adelta-afferent fibres from different segmental dorsal roots on to single substantia gelatinosa neurones in the rat spinal cord. J Physiol 586:4165-77
Saneyoshi, Takeo; Wayman, Gary; Fortin, Dale et al. (2008) Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron 57:94-107

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