Actions of phenylglycine derivatives at L-AP4 receptors in retinal ON bipolar cells

Phenylglycine derivatives can act as agonists or antagonists at different metabotropic glutamate receptor (mGluR) subtypes, including subtypes sensitive to l-2-amino-4-phosphonobutyric acid (L-AP4). We examined the pharmacology of four phenylglycines at L-AP4 receptors in ON bipolar 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-4hydroxyphenylglycine (S-3C4H-PG) and S-4-carboxyphenylglycine (S-4C-PG) are L-AP4 receptor agonists in retina. Concentration-response curves for these compounds were obtained using the b-wave of the electroretinogram (ERG) as an assay for ON bipolar cell activity. The rank-order potency and IC₅₀ values obtained were: S-4C-PG (204 μM) > S-4C3H-PG (399 μM) ≥ S-3C4H-PG (558 μM). At 1 mM, RS-α-methyl4-carboxyphenylglycine (RS-M4C-PG) suppressed the b-wave by less than 20%. This weak effect is attributed to agonist actions of RS-M4C-PG. The agonist actions of phenylglycines in retina are different from their effects at L-AP4 receptors in spinal cord or the expressed L-AP4-sensitive receptor subtype, mGluR4 (Kemp et al, Eur. J. Pharmac. Molec. Pharmac., 266, 187-192, 1994; Thomsen et al., Eur. J. Pharmac. Molec. Pharmac., 267, 77-84, 1994; Hayashi et al., J. Neurosci., 14, 3370-3377, 1994). The results are therefore consistent with the proposal that there are multiple L-AP4-sensitive mGluR sybtypes and indicate that phenylglycine derivatives may be useful for pharmacologically discriminating among these sybtypes.