title: Metabotropic glutamate receptor-mediated suppression of an inward rectifier current is linked via a cGMP cascade.
abstract: Glutamate, the neurotransmitter released by photoreceptors, excites horizontal cells and OFF-type bipolar cells by activating ionotropic receptors. This study investigated an additional action of glutamate in which it modulates a voltage-gated ion channel in horizontal cells. We find that glutamate and APB (2-amino-4-phosphonobutyrate) produce a delayed and moderately prolonged suppression of an inward rectifier current (IRK+). This effect is proposed to occur via an APB-sensitive metabotropic glutamate receptor (mGluR) because common agonists for the ionotropic or APB-insensitive mGluRs are ineffective and the APB-insensitive receptor antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) does not block the actions of glutamate or APB. 8-Br-cGMP, 1-methyl-3-isobutylxanthine (IBMX), and atrial natriuretic peptide (ANP) but not 8-Br-cAMP mimic the suppression of IRK+. The effects of glutamate and APB are blocked by protein kinase inhibitors including Rp-8-pCPT-cGMPS, H-8, and H-7 as well as by ATPgammaS. We hypothesize that the APB receptor suppresses IRK+ via upregulation of cGMP and subsequent activation of a cGMP-dependent protein kinase. This pathway is likely regulated by an ATP-dependent phosphorylation. This is a novel signaling pathway for mGluRs and indicates that at least two distinct APB-activated pathways exist in the retina. Functionally, this APB receptor-mediated action found in horizontal cells would provide a means by which spatially restricted changes of glutamate, produced by local illumination of photoreceptors, could regulate IRK+ and consequently the response properties of these neurons. This would serve to adapt selectively retinal regions stimulated by small regions of the visual world.
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, California 94143, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Dixon
authors.forename: D R
authors.initials: DR
authors.lastname: Copenhagen
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007059:Ictaluridae; D015640:Ion Channel Gating / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D010786:Photoreceptor Cells / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D000613:Aminobutyrates; D001565:Benzoates; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D015221:Potassium Channels; D018094:Receptors, Metabotropic Glutamate; D013873:Thionucleotides; C079694:alpha-methyl-4-carboxyphenylglycine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; C022571:adenosine 5'-O-(3-thiotriphosphate); D018698:Glutamic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D009320:Atrial Natriuretic Factor; D000255:Adenosine Triphosphate; D006152:Cyclic GMP; C012729:2-amino-4-phosphonobutyric acid; D015056:1-Methyl-3-isobutylxanthine; D005998:Glycine