Abstract
Several potent and selective agonists of the glutamate (L-GLU) receptors of N-methyl-D-aspartate (NMDA) type have been tested on the L-[3H]GLU binding to rat cortical membranes, on the depolarization of mouse cortical wedges and on the contraction of guinea pig longitudinal muscle myenteric plexus preparations with the aim of comparing the NMDA receptors present in the cortex and those present in the gut.
When the depolarization of the cortical wedges was evaluated, the EC50 values of the agonists were (μM): (R,S)-(tetrazol-5-yl)-glycine (TG) 0.3; trans-4-hydroxy (S)-pipecolic acid-4-sulfate (t-HPIS) 0.7; 1-aminocyclobutane-cis-1,3-dicarboxylic acid (ACBD) 0.8; NMDA 8; (2S,3R,4S) cyclopropylglutamate (L-CGA C) 12; quinolinic acid (QUIN) 400. When the contraction of the longitudinal muscle myenteric plexus was evaluated, the EC50 values were (μM): L-CGA C 1; TG 8; ACBD 50; t-HPIS 100; QUIN 500 and NMDA 680. When the displacement of NMDA specific L-[3H]GLU binding from rat cortical membranes was evaluated, the IC50 values were (NM): L-CGA C 0.003; TG 0.005; ACBD 0.044; t-HPIS 0.062; NMDA 0.31 and QUIN 15. No significant correlation was found when the EC50 values obtained in the ileum were plotted against the EC50 values obtained in the cortex (r = 0.47). In particular it was noted that L-CGA C was approximately three orders of magnitude more potent than NMDA when tested in the ileum but had a potency not significantly different from that of NMDA when tested in the cortex. On the contrary, t-HPIS was particularly potent in cortical wedges.
The results of these experiments suggest that different populations of NMDA receptors are present in the tissues of the three mammalian species investigated. In particular, the receptors present in the mouse cortical wedges are selectively stimulated by t-HPIS while those present in the guinea pig myenteric plexus are preferentially stimulated by L-CGA C. Thus at least two functional subtypes of NMDA receptors may be identified in mammalian tissues by using the order of potency of selective agonists.
Similar content being viewed by others
References
Ahlquist RP (1948) A study of adrenotropic receptors. Am J Physiol 153:586–600
Broussard DL, Li X, Pritchett DB, Bannerman PGC, Pleasure D (1993) The expression of an NMDA receptor gene in the guinea pig myenteric plexus. Soc Neurosci Abstr 19:1356
Burton NR, Smith DAS, Stone TW (1988) A quantitative pharmacological analysis of some excitatory amino acid receptors in the mouse neocortex “in vitro”. Br J Pharmacol 93: 693–701
Collingridge GL, Lester RAJ (1989) Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 41:143–210
De Lean A, Munson PJ, Rodbard D (1978) Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay and physiological dose-response curves. Am J Physiol 235:E97–102
Durand GM, Bennett MVL, Zukin S (1993) Splice variants of the NMDA receptor NRl identify domains involved in regulation by polyamines and protein kinase C. Proc Natl Acad Sci USA 90:6731–6735
Evans SV, Shing TKM, Aplin RT, Fellows LE, Fleet GWJ (1985) Sulphate ester of trans-4-hydroxypipecolic acid in seeds of Peltophorum. Phytochemistry 24:2593–2598
Foster AC, Collins JF, Schwarcz R (1983) On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds. Neuropharmacology 22:1331–1335
Fowden L, Smith A, Millington DS, Sheppard RC (1969) Cyclopropane amino acids from Aescules and Blighia. Phytochemistry 8:437–443
Harrison NL, Simmonds MA (1985) Quantitative studies on some antagonists of NMDA in slices of rat cerebral cortex. Br J Pharmacol 84:381–391
Hollmann M, Boulter J, Maron C, Beasley L, Sullivan J, Pecht G, Heinemann S (1993) Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 10:943–954
Kenakin TP (1987) Agonist efficacy. In: Kenakin TP (ed) Pharmacologic analysis of drug-receptor interaction. Raven Press, New York, pp 183–204
Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M, Mishina M (1992) Molecular diversity of the NMDA receptor channel. Nature 358:36–41
Lanthorn TH, Hood WF, Watson GB, Compton RP, Rader RK, Gaoni Y, Monahan JB (1990) Cis-2,4-methanoglutamate is a potent and selective NMDA receptor agonist. Eur J Pharmacol 182:397–404
Luzzi S, Zilletti L, Franchi-Micheli S, Gori AM, Moroni F (1988) Agonists, antagonists and modulators of excitatory amino acid receptors in the guinea-pig myenteric plexus. Br J Pharmacol 95:1271–1277
Mannaioni G, Alesiani M, Carla' V, Natalini B, Marinozzi M, Pellicciari R, Moroni F (1994) Sulfate esters of hydroxy amino acids as stereospecific glutamate receptor agonists. Eur J Pharmacol 251:201–207
Mayer HL, Westbrook GL (1987) The physiology of excitatory amino acids in the central nervous system. Prog Neurobiol 28:197–276
Monaghan DT (1991) Differential stimulation of 3H-MK801 binding to subpopulations of NMDA receptors. Neurosci Lett 122:21–24
Monaghan DT, Olverman HJ, Nguyen L, Watkins JC, Cotman CW (1988) Two classes of NMDA recognition sites: differential distribution and differential regulation by glycine. Proc Natl Acad Sci USA 85:9836–9840
Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221
Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizumo N, Nakanishi S (1991) Molecular cloning and characterization of the rat NMDA receptor. Nature 354:31–37
Moroni F, Lombardi G, Carla' V, Moneti G (1984) The excitotoxin quinolinic acid is present and unevenly distributed in the rat brain. Brain Res 295:352–355
Moroni F, Luzzi S, Franchi-Micheli S, Zilletti L (1986) The presence of NMDA-type receptors for glutamic acid in the guinea-pig myenteric plexus. Neurosci Lett 68:57–62
Moroni F, Alesiani M, Galli A, Mori F, Pecorari R, Carla' V, Cherici G, Pellicciari R (1991) Thiokynurenates: a new group of antagonists of the glycine modulatory site of the NMDA receptors. Eur J Pharmacol 199:227–232
Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–602
Nakamura Y, Kataoka K, Ishida M, Shinozaki H (1993) (2S,3S,4R)2-(carboxycyclopropyl)glycine a potent and competitive inhibitor of both glial and neuronal uptake of glutamate. Neuropharmacology 32:833–837
Paton WDM, Zar MA (1968) The origin of acethylcholine released from the guinea pig small intestine and longitudinal muscle strips. J Physiol 194:13–32
Pellicciari R, Curini M, Natalini B, Ceccherelli P (1986) Preparation of cyclopropylglutamic analogs. In: IX International symposium on Medicinal Chemistry, p 118
Pellicciari R, Natalini R, Luneia R, Marinozzi M, Roberti M, Rosato GC, Sadeghpour BM, Snyder JP, Monahan JB, Moroni F (1992) Enantioselective synthesis of naturally occurring trans-4-hydroxy-(S)-pipecolic acid-4 sulfate, a new potent and selective NMDA receptor agonist. Med Chem Res. 2:491–496
Pellicciari R, Natalini B, Marinozzi M, Selvi L, Chioni C, Monahan JB, Lanthorn TH, Snyder J (1988) 3,4-cyclopropylglutamate as conformation ally restricted agonist of the NMDA receptor. In: Cavalheiro EA, Lehman S, Turski L (eds) Frontiers in excitatory amino acid research. Alan Liss, New York, pp 67–70
Perkins MN, Stone TW (1983) Quinolinic acid: regional variations in neuronal sensitivity. Brain Res 259:172–176
Quarum ML, Parker JD, Keana JFW, Weber E (1990) 3H-MK801 binding sites in postmortem human brain. J Neurochem 54:1163–1168
Schoepp DD, Smith CL, Lodge D, Millar JD, Leander JD, Sacaan AI, Lunn WHW (1991) D,L-(tetrazol-5-yl) glycine: A novel and highly potent NMDA receptor agonist. Eur J Pharmacol 203:237–243
Seeburg PH (1993) The molecular biology of mammalian glutamate receptor channels. Trends Pharmacol Sci 16:359–365
Shinozaki H, Ishida M, Shimamoto K (1989) Potent NMDA-like actions and potentiation of glutamate responses by conformational variants of a glutamate analogue in the rat spinal cord. Br J Pharmacol 98:1213–1224
Standaert DG, Testa CM, Penney JB Jr, Young AB (1993) Alternatively spliced isoforms of the NMDAR1 glutamate receptor subunit: differential expression in the basal ganglia of the rat. Neurosci Lett 152:161–164
Sugihara H, Moriyoshi K, Ishii T, Masu M, Nakanishi S (1992) Structures and properties of seven isoforms of the NMDA receptor generated by alternative splicing. Biochem Biophys Res Commun 185:826–832
Tallarida RJ, Murray R (1984) Manual of pharmacologic calculation with computer programs. Springer, Berlin
Yoneda Y, Ogita K (1991) Heterogeneity of the NMDA receptor ionophore complex in rat brain, as revealed by ligand binding techniques. J. Pharmacol Exp Ther 259:86–96
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Moroni, F., Galli, A., Mannaioni, G. et al. NMDA receptor heterogeneity in mammalian tissues: focus on two agonists, (2S,3R,4S) cyclopropylglutamate and the sulfate ester of 4-hydroxy-(S)-pipecolic acid. Naunyn-Schmiedeberg's Arch Pharmacol 351, 371–376 (1995). https://doi.org/10.1007/BF00169077
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00169077