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

Wallace B. Thoreson, Joseph S. Ulphani

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)93-102
Number of pages10
JournalBrain Research
Volume676
Issue number1
DOIs
StatePublished - Apr 3 1995

Keywords

  • APB
  • Electroretinogram
  • Metabotropic glutamate receptor
  • ON bipolar cell
  • Whole cell recording
  • l-2-Amino-4-phosphonobutyric acid

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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