Structural requirements for activation of excitatory amino acid receptors in the rat spinal cord in vitro.
The conformational requirements for activation of N-methyl-D-aspartate (NMDA) and quisqualate (QUIS) excitatory amino acid receptors on rat spinal neurones in vitro have been examined using a number of conformationally restricted compounds related to L-glutamate (L-GLU). The excitants were assigned to a receptor type on the basis of their susceptibility to blockade by D (-)-2-amino-5-phosphonvalerate (DAPV) and kynurenate (KYNA). When iontophoretically applied to unidentified neurones in the dorsal horn of spinal cord slices maintained in vitro, three of the isomers of 1-amino-1,3-cyclopentane dicarboxylate (ACPD) evoked excitations which were DAPV-sensitive and therefore were probably elicited via NMDA receptors. The fourth isomer (D-trans-(1R,3S)-ACPD) resembled quinolinate (QUIN) in its actions, and differed from both NMDA and QUIS. Several pyridine derivatives in addition to QUIN were tested, and both the 2,5- and 2,6-pyridine dicarboxylates evoked excitations which, like those produced by QUIS and L-GLU, were largely unaffected by both DAPV and KYNA and thus appeared due to activation of the QUIS receptor. 2,4-Pyridine dicarboxylate acted as a weak and unselective antagonist of amino acid-induced excitations. The results support an earlier conclusion that compounds reacting with the NMDA receptor do so in an extended configuration whereas the QUIS receptor has a more folded template. The possibility that QUIN reacts with a receptor different from those activated by other amino acids is considered.
Magnuson
D S
DS
Department of Physiology, University of British Columbia, Vancouver, Canada.
Curry
K
K
Peet
M J
MJ
McLennan
H
H
D015763:2-Amino-5-phosphonovalerate; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D014633:Valine