Pharmacology of selective and non-selective metabotropic glutamate receptor agonists at L-AP4 receptors in retinal ON bipolar cells.

Retinal ON bipolar cells possess metabotropic glutamate receptors (mGluRs) which are sensitive to L-2-amino-4-phosphonobutyric acid (L-AP4). Recent studies suggest there are multiple subtypes of L-AP4 receptors. In order to provide a more complete description of the pharmacology of the retinal L-AP4 receptor, we examined the actions of a number of compounds which are active at L-AP4 receptors and other mGluRs. Four groups of compounds were studied: (1) AP4 analogues (e.g. L-AP5, L-SOP, cyclobutylene AP5, and N-Me-AP4), (2) non-selective mGluR agonists (ibotenate and quisqualate), (3) selective mGluR agonists (L-CCG-I), and (4) agonists proposed to be selective for specific mGluR subtypes (DCG-IV and t-ADA). Concentration-response curves were obtained using the b-wave of the electroretinogram (ERG) as an assay for L-AP4 receptor activation. Whole cell voltage clamp recordings from ON bipolar cells in the retinal slice preparation of the mudpuppy were used to determine whether the compounds acted as L-AP4 receptor agonists. All compounds were L-AP4 receptor agonists, except t-ADA which was ineffective. The results reveal pharmacological differences between L-AP4 receptors in mudpuppy ON bipolar cells and those in other systems, consistent with the proposal that there are multiple L-AP4 receptor subtypes. For example, retinal L-AP4 receptors are more potently activated by L-AP5 than L-SOP, whereas L-SOP has been shown to be more potent than L-AP5 in L-AP4 receptors in the lateral perforant path (LPP) of the rat hippocampus. L-SOP is also relatively more potent at the cloned L-AP4 receptors mGluR4, 6, and 7 than in mudpuppy ON bipolar cells in situ. The different potencies of these compounds in retina and LPP is ascribed to both steric and charge factors. The results with DCG-IV and t-ADA are consistent with the proposal that these are subtype-selective agonists, but DCG-IV is likely to be selective only at very low concentrations (< or = 1 microM).