TY - JOUR
T1 - Pharmacology of selective and non-selective metabotropic glutamate receptor agonists at l-AP4 receptors in retinal ON bipolar cells
AU - Thoreson, Wallace B.
AU - Ulphani, Joseph S.
N1 - Funding Information:
This work was supported by the Gifford Laboratory of Ophthalmology. We thank Drs. H. Shinozaki, A.P.
PY - 1995/4/3
Y1 - 1995/4/3
N2 - 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).
AB - 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).
KW - APB
KW - Electroretinogram
KW - Metabotropic glutamate receptor
KW - ON bipolar cell
KW - Whole cell recording
KW - l-2-Amino-4-phosphonobutyric acid
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U2 - 10.1016/0006-8993(95)00093-6
DO - 10.1016/0006-8993(95)00093-6
M3 - Article
C2 - 7796182
AN - SCOPUS:0028965160
SN - 0006-8993
VL - 676
SP - 93
EP - 102
JO - Brain Research
JF - Brain Research
IS - 1
ER -