Acid (1S,3R-ACPD) in Retinal ON Bipolar Cells Indicate That It Is an Agonist at L-AP4 Receptors

Metabotropic glutamate receptors (mGluRs) include receptors sensitive to L-2-amino-4-phosphonobutyrate (L-AP4) and 1S,3R-l-aminocyclopentane1,3-dicarboxylic acid (1S,3R-ACPD). To determine whether 1S,3R-ACPD is an agonist at retinal L-AP4 receptors, whole cell voltage clamp recordings were obtained from mudpuppy ON bipolar cells in a superfused retinal slice and L-AP4 and 1S,3R-ACPD were bath applied. Both compounds evoked similar outward currents which reversed near 0 mV and were accompanied by an increased input resistance. Responses to both agonists washed out in parallel suggesting they act through the same second messenger pathway(s). Inhibitors of cGMP-PDE activity suppressed responses to both L-AP4 and 1SR,3RS-ACPD, suggesting that both compounds activate cGMP-PDE. Responses to 1S,3R-ACPD were occluded by prior activation of L-AP4 receptors, but not blocked by the non-AP4, mGluR antagonists, L-aminophosphonopropionic acid (L-AP3) or 4-carboxy-3-hydroxyphenylglycine (4C3H-PG). These results indicate that 1S,3R-ACPD is an agonist at L-AP4 receptors. 1S,3S-ACPD and 4C3H-PG evoked outward currents similar to L-AP4 suggesting they may also be L-AP4 receptor agonists. Using the b-wave of the ERG as an assay for ON bipolar cell responses, concentration/response curves were obtained for ACPD enantiomers. The rank-order potency of ACPD enantiomers at L-AP4 receptors in ON bipolar cells is similar to their rank-order potency at non-AP4, mGluRs in brain which suggests that the receptors possess similar binding sites and may be members of a common receptor family. I N T R O D U C T I O N The amino acid, L-glutamate, is the major excitatory neurotransmitter in the brain, spinal cord, and retina. The effects of glutamate are mediated by two general classes of receptors: (a) ionotropic receptors which are coupled directly to ion channels and include N-methyl-D-aspartate (NMDA), ot-amino-3-hydroxy-5-methylisoxazole-4-proAddress correspondence to Wallace B. Thoreson at his present address: Department of Ophthalmology, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE 68198-5540. J. GEN. PHYSIOL. 9 The Rockefeller University Press. 0022-1295/94/06/1019/16 $2.00 Volume 103 June 1994 1019-1034 1019 on Jne 9, 2017 D ow nladed fom Published June 1, 1994