Evidence for the expression of multiple subtypes of excitatory amino acid receptors coupled to phosphoinositide hydrolysis in the mammalian central nervous system

Louis Littman, University of Pennsylvania

Abstract

L-Glutamate (L-Glu) and L-aspartate (L-Asp) are the major excitatory neurotransmitters in the mammalian brain. These excitatory amino acids (EAAs) stimulate receptors coupled to ion channels and receptors coupled to second messenger systems. The purpose of these studies was to examine the pharmacological properties of EAA receptors coupled to phosphoinositide (PI) hydrolysis to determine if subtypes of these receptors are functionally expressed in the brain. To differentiate receptor subtypes, specific receptor antagonists must be identified. To explore the effects of antagonists, however, it is first necessary to determine the properties of agonists of these receptors. Therefore, the effects of L-Glu, L-Asp, D-Asp, quisqualate, ibotenate, and trans-1-amino-1,3-cyclopentanedicarboxylate (trans-ACPD) on the stimulation of PI hydrolysis in hippocampus or cerebellum were measured. There was a high correlation (r = 0.96) between the effects of these compounds in hippocampus and the effects of these compounds in cerebellum. PI hydrolysis stimulated by EAA analogs in hippocampus was blocked by 2-amino-3-phosphonopropionate (AP3). The effects of AP3 were consistent with an irreversible, non-competitive mechanism of action. L-aspartate-$\beta$-hydroxamate (L-A$\beta$HA) was identified as another inhibitor of PI hydrolysis stimulated by EAA analogs. Data for inhibition by L-A$\beta$HA were also consistent with an irreversible, non-competitive mechanism of action in hippocampus. Although AP3 and L-A$\beta$HA blocked PI hydrolysis stimulated by EAA analogs in hippocampus, both AP3 and L-A$\beta$HA stimulated PI hydrolysis in cerebellum. These data suggest that EAA receptor subtypes coupled to PI hydrolysis in hippocampus are different from those in cerebellum. The effects of trans-ACPD, quisqualate, ibotenate, D-Asp, or L-Asp, but not the effects of L-Glu, in either hippocampus or cerebellum were blocked by (+)-$\alpha$-methyl-4-carboxyphenylglycine ((+)-MCPG). The effects of (+)-MCPG were consistent with a competitive mechanism of action. These data suggest that trans-ACPD and L-Asp activate receptors distinct from those activated by L-Glu. The current studies therefore provide evidence for the expression of multiple EAA receptor subtypes coupled to PI hydrolysis in the mammalian brain.

Subject Area

Pharmacology|Neurology

Recommended Citation

Littman, Louis, "Evidence for the expression of multiple subtypes of excitatory amino acid receptors coupled to phosphoinositide hydrolysis in the mammalian central nervous system" (1994). Dissertations available from ProQuest. AAI9427568.
https://repository.upenn.edu/dissertations/AAI9427568

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