Polyamine regulation of N-methyl-D-aspartate channels.
dc.contributor.author | Rock, David Michael | en_US |
dc.contributor.advisor | Macdonald, Robert L. | en_US |
dc.date.accessioned | 2014-02-24T16:23:09Z | |
dc.date.available | 2014-02-24T16:23:09Z | |
dc.date.issued | 1995 | en_US |
dc.identifier.other | (UMI)AAI9542946 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9542946 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/104697 | |
dc.description.abstract | Endogenous polyamines such as spermine (SP) and spermidine (SD) have multiple effects in the central nervous system and have been suggested to be neurotransmitters or neuromodulators. One effect of polyamines is to regulate the activity of the N-methyl-D-aspartate (NMDAR) subtype of glutamate receptor channels. Polyamines have been shown to have multiple actions on NMDAR channels. While receptor binding experiments suggest that polyamines enhanced binding of open-channel blockers to the NMDAR channel through a site distinct from other regulatory sites on the receptor channel, electrophysiological experiments outlined in this thesis indicate that the multiple actions of polyamines are difficult to explain by an action at a single site. The polyamine agonist SP enhanced NMDAR whole-cell currents by increasing channel opening frequency and also inhibited NMDAR whole-cell currents in a voltage-dependent manner. The inhibitory action of SP occurred by an interaction near or at the opening of the ion channel and led to a biphasic concentration-response relationship for the effect of SP on NMDAR whole-cell currents. The other polyamine agonist, SD, had similar effects on NMDAR channels. The polyamine antagonists diethylenetriamine (DET), putrescine (PUT) and arcaine (ARC) inhibited NMDAR whole-cell and single-channel currents in the absence of polyamine agonists. The mechanism for these inhibitory actions of DET and PUT were similar to that of SP indicating that these polyamine antagonists acted at the same site or sites as SP. ARC and inverse agonists diaminodecane and diaminododecane reduced NMDAR single channel currents by a channel block mechanism, an action that was not opposite to the enhancing action of SP. These data suggest that polyamines interact with multiple sites on NMDAR channels to exert their action. Interaction at one site leads to an enhancement of NMDAR currents by increasing channel opening frequency, while interactions around the opening of the channel pore (polyamine agonists and antagonists) or in the channel (inverse agonists) lead to inhibitory actions. Classification of polyamines as agonists, antagonists and inverse agonists should be reconsidered in light of these data. | en_US |
dc.format.extent | 174 p. | en_US |
dc.subject | Biology, Neuroscience | en_US |
dc.subject | Health Sciences, Pharmacology | en_US |
dc.subject | Biophysics, General | en_US |
dc.title | Polyamine regulation of N-methyl-D-aspartate channels. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Neuroscience | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/104697/1/9542946.pdf | |
dc.description.filedescription | Description of 9542946.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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