Franklin

Pharmacological and physiological characterization of recombinant and native NMDA receptors [electronic resource].

Author/Creator:
Kendrick, Shelley Jean.
Format/Description:
Book
187 p.
Contained In:
Dissertation Abstracts International 58-03B.

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Details

Subjects:
Pharmacology.
Neurosciences.
Molecular biology.
Local subjects:
Penn dissertations -- Pharmacology. (search)
Pharmacology -- Penn dissertations. (search)
System Details:
Mode of access: World Wide Web.
Summary:
The NMDA receptor is a ligand gated ion channel involved in many physiological and pathophysiological processes. A key element in understanding the NMDA receptor is to determine the molecular basis of the receptor's pharmacological and functional properties. The cDNAs encoding the subunits which comprise the NMDA receptor have been cloned and fall into two main families: the NR1 family, which includes eight splice variants and the NR2 family, which include four related subunits, 2A-2D. This thesis examines the properties of the NMDA receptor subunits and how they relate to native NMDA receptor subtypes through ligand binding and electrophysiological assays on recombinant NMDA receptors expressed in HEK 293 cells and native NMDA receptors expressed in adult rat brain and cultured hippocampal neurons. We find that with respect to channel blocking agents the receptor formed by NR1a2B resembles the receptors formed from NR1a2A subunits. However, potentiation of NMDA response by Mg$\sp{++}$ and inhibition by ifenprodil appears to distinguish between NR2A- and NR2B-containing receptors. With respect to the transmitter recognition site, we demonstrate that the NR2A subunit alone is sufficient to create a high affinity agonist site whereas a high-affinity antagonist binding site requires interactions between an NR1 subunit and an NR2 subunit. In addition, we demonstrate that different NR2 subunits in complex with NR1 can confer variability in the glutamate binding site. However, we also demonstrate non-equivalent glutamate sites within heteromeric transfections may also account for heterogeneity of the glutamate site in native NMDA receptors. In addition, we show that Mg$\sp{++}$ can alter antagonist binding in both NR1a2A and NR1a2B heteromeric complexes. With respect to desensitization properties of the NMDA receptor, our results suggest that recombinant receptors expressed in HEK 293 cells resemble native NMDA receptors with respect to glycine's effect on desensitization but do not exhibit Ca$\sp{++}$-sensitive desensitization. In addition, we demonstrate that subtypes of NMDA receptors can exist within one neuron and can be selectively activated by varying the glycine concentration.
Notes:
Thesis (Ph.D. in Pharmacology) -- University of Pennsylvania, 1997.
Source: Dissertation Abstracts International, Volume: 58-03, Section: B, page: 1231.
Local notes:
School code: 0175.
Contributor:
University of Pennsylvania.
ISBN:
9780591363142
Access Restriction:
Restricted for use by site license.