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, cyclobutylenee 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 receptorsagonists, 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 retinal 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 (≤ 1 μM).
Brain Research – Elsevier
Published: Apr 3, 1995
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