ACTIONS OF PHENYLGLYCINE DERIVATIVES AT L-AP4 RECEPTORS IN RETINAL ONBIPOLAR CELLS

Phenylglycine derivatives can act as agonists or antagonists at differ ent metabotropic glutamate receptor (mGluR) subtypes, including subtyp es sensitive to L-2-amino-4-phosphonobutyric acid (L-AP4). We examined the pharmacology of four phenylglycines at L-AP4 receptors in ON bipo lar cells of the amphibian retina in situ. As previously shown for S-4 -carboxy-3-hydroxyphenylglycine (S-4C3H-PG) (Thoreson W. B. and Miller R. F., J. Gen. Physiol. 103, 1019-1034, 1994), whole cell recordings indicate that S-3-carboxy-4-hyroxyphenylglycine (S-3C4H-PG) and S-4-ca rboxyphenylglycine (S-4C-PG) are L-AP4 receptor agonists in retina. Co ncentration-response curves for these compounds were obtained using th e b-wave of the electroretinogram (ERG) as an assay for ON bipolar cel l activity. The rank-order potency and IC50 values obtained were: S-4C -PG (204 mu M) > S-4C3H-PG (399 mu M) greater than or equal to S-3C4H- PG (558 mu M). At 1 mM, RS-alpha-methyl-4-carboxyphenylglycine (RS-M4C -PG) suppressed the b-wave by less than 20%. This weak effect is attri buted to agonist actions of RS-M4C-PG. The agonist actions of phenylgl ycines in retina are different from their effects at L-AP4 receptors i n spinal cord or the expressed L-AP4-sensitive receptor subtype, mGluR 4 (Kemp et al., Eur. J. Pharmac. Molec. Pharmac., 266, 187-192, 1994; Thomsen et al., Eur. J. Pharmac. Molec. Pharmac., 267, 77-84, 1994; Ha yashi et al., J. Neurosci., 14, 3370-3377, 1994). The results are ther efore consistent with the proposal that there are multiple L-AP4-sensi tive mGluR sybtypes and indicate that phenylglycine derivatives may be useful for pharmacologically discriminating among these sybtypes.