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Regulation of postsynaptic AMPA receptor trafficking by MAPK pathways in Caenorhabditis elegans neurons
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Title
Regulation of postsynaptic AMPA receptor trafficking by MAPK pathways in Caenorhabditis elegans neurons
Name
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Park
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Eunchan
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Eunchan Park
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author
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Rongo
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Christopher
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Advisory Committee
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Christopher Rongo
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chair
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Driscoll
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Monica
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Advisory Committee
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Monica Driscoll
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internal member
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Firestein
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Bonnie
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Advisory Committee
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Bonnie L. Firestein
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internal member
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Padgett
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Richard
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Advisory Committee
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Richard W. Padgett
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(authority = RULIB)
internal member
Name
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Singson
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Andrew
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Advisory Committee
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Andrew Singson
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outside member
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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theses
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2008
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2008-01
Language
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English
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electronic
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xi, 166 pages
Abstract
AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate)-type glutamate receptors mediate the majority of the rapid ongoing excitatory neurotransmission in the brain. The spatio-temporal regulation of AMPA receptor trafficking, which includes endocytosis and recycling, is a crucial process for synaptic plasticity, and is therefore important for learning and memory. Signaling cascades, including the MAPK pathways, have been implicated in the regulation of synaptic plasticity in mammals. However, little is known about the molecular mechanisms by which MAPK pathways regulate AMPA receptor trafficking. In C. elegans, the AMPA receptor subunit GLR-1 is trafficked to synapses within a circuit that regulate locomotion reversal. GLR-1 undergoes clathrin-dependent endocytosis, and its recycling is mediated by the PDZ protein LIN-10; mutations in lin-10 result in the accumulation of GLR-1 in an internal compartment. From the screening of genetic modifiers of lin-10, we identified mutations in rpm-1 as an enhancer of lin-10. We find that RPM-1, an E3 ubiquitin ligase, negatively regulates PMK-3 (p38 MAPK) activity by decreasing upstream DLK-1(MAPKKK) levels, and that PMK-3 is involved in clathrin-dependent/RAB-5-mediated endocytosis of GLR-1. However, intriguingly, the loss of function mutations of two known components of PMK-3 pathways, dlk-1(mapkkk) and mkk-4 (mapkk), do not suppress GLR-1 accumulation, unlike the mutations of pmk-3. By examining other known MAPKKs in C. elegans, we find that mutations in jkk-1 suppress the GLR-1 accumulation in lin-10 mutants, similar to mutations in pmk-3. Moreover, we find that mutations in sek-1, another MAPKK, result in the accumulation of GLR-1. Finally, by examining the orthologs of Ras family protein known to function upstream of MAPK pathways in mammals, we find that RAP-1 regulates GLR-1 trafficking. Taken together, our results suggest that multiple MAPK pathways regulate AMPA receptor trafficking, sometimes with opposite outcomes. Moreover, our results indicate that there is crosstalk between MAPK pathways, and that factors like RPM-1 act to regulate such crosstalk.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references (p. 148-165).
Subject
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Topic
Neuroscience
Subject
(ID = SUBJ2);
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Topic
Neurotransmitter receptors
Subject
(ID = SUBJ3);
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Topic
Neurons
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17210
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ETD_714
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NjNbRU
Identifier
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doi:10.7282/T31836V0
Genre
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ETD doctoral
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Rights
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The author owns the copyright to this work.
Copyright
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Copyright protected
Availability
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Open
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Name
EUNCHAN PARK
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Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Permission or license
Detail
Non-exclusive ETD license
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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