NMDA RECEPTOR HETEROGENEITY IN MAMMALIAN-TISSUES - FOCUS ON 2 AGONISTS, (2S, 3R, 4S) CYCLOPROPYLGLUTAMATE AND THE SULFATE ESTER OF 4-HYDROXY-(S)-PIPECOLIC ACID

Several potent and selective agonists of the glutamate (L-GLU) recepto rs of N-methyl-D-aspartate (NMDA) type have been tested on the L-[H-3] GLU binding to rat cortical. membranes, on the depolarization of mouse cortical wedges and on the contraction of guinea pig longitudinal mus cle myenteric plexus preparations with the aim of comparing the NMDA r eceptors present in the cortex and those present in the gut. When the depolarization of the cortical wedges was evaluated, the EC(50) values of the agonists were (CIM): (R,S)-(tetrazol-5-yl)-glycine (TG) 0.3; t rans-4-hydroxy-(S)-pipecolic acid-4-sulfate (t-HPIS) 0.7; 1-aminocyclo butane-cis- 1,3-dicarboxylic acid (ACBD) 0.8, NMDA 8; (2S,3R,4S) cyclo propylglutamate (L-CGA C) 12; quinolinic acid (QUIN) 400. When the con traction of the longitudinal muscle myenteric plexus was evaluated, th e EC,, values were (mu M): L-CGA C 1; TG 8; ACBD 50; t-HPIS 100; QUIN 500 and NMDA 680. When the displacement of NMDA specific L-[H-3]GLU bi nding from rat cortical membranes was evaluated, the IC50 values were (mu M): L-CGA C 0.003; TC 0.005; ACBD 0.044; t-HPIS 0.062; NMDA 0.31 a nd QUIN 15. No significant correlation was found when the EC(50) value s obtained in the ileum were plotted against the EC,, 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 tes ted in the ileum but had a potency not significantly different from th at of NMDA when tested in the cortex. On the contrary, t-HPIS was part icularly potent in cortical wedges. The results of these experiments s uggest that different populations of NMDA receptors are present in the tissues of the three mammalian species investigated. In particular, t he receptors present in the mouse cortical wedges are selectively stim ulated by t-HPIS while those present in the guinea pig myenteric plexu s are preferentially stimulated by L-CGA C. Thus at least two function al subtypes of NMDA receptors may be identified in mammalian tissues b y using the order of potency of selective agonists.