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

Pharmacology of selective and non-selective metabotropic glutamate receptor agonists at l -AP4... 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). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Research Elsevier

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

Brain Research, Volume 676 (1) – Apr 3, 1995

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Publisher
Elsevier
Copyright
Copyright © 1995 Elsevier Science B.V. All rights reserved
ISSN
0006-8993
D.O.I.
10.1016/0006-8993(95)00093-6
Publisher site
See Article on Publisher Site

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).

Journal

Brain ResearchElsevier

Published: Apr 3, 1995

References

  • Agonist analysis of 2-(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate receptor subtypes expressed in Chinese hamster ovary cells
    Hayashi, Y.; Tanabe, Y.; Aramori, I.; Masu, M.; Shimamoto, K.; Ohfune, Y.; Nakanishi, S.
  • Muscarinic activation of ionic currents measured by a new whole-cell recording method
    Horn, R.; Marty, A.
  • A novel metabotropic glutamate receptor agonist: marked depression of monosynaptic excitation in the newborn rat isolated spinal cord
    Ishida, M.; Saitoh, T.; Shimamoto, K.; Ohfune, Y.; Shinozaki, H.
  • Voltage- and transmitter-gated current in isolated rod bipolar cells of rat retina
    Karschin, A.; Wässle, H.
  • The ON and OFF channels of the visual system
    Schiller, P.
  • B-wave of the electroretinogram: A reflection of ON bipolar cell activity
    Stockton, R.A.; Slaughter, M.M.
  • Membrane currents evoked by excitatory amino acid agonists in ON bipolar cells of the mudpuppy retina
    Thoreson, W.B.; Miller, R.F.

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