Metabotropic Glutamate Receptor-Mediated Suppression of an Inward Rectifier Current Is Linked via a cGMP Cascade

• Published in: The Journal of neuroscience Vol. 17; no. 23; pp. 8945 - 8954
• Main Authors: Dixon, Don B, Copenhagen, David R
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.12.1997; Society for Neuroscience
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 1-Methyl-3-isobutylxanthine - pharmacology; 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Aminobutyrates - pharmacology; Animals; Atrial Natriuretic Factor - pharmacology; Benzoates - pharmacology; Cyclic GMP - analogs & derivatives; Cyclic GMP - pharmacology; Cyclic GMP - physiology; Enzyme Inhibitors - pharmacology; Glutamic Acid - pharmacology; Glycine - analogs & derivatives; Glycine - pharmacology; Ictaluridae; Ion Channel Gating - drug effects; Isoquinolines - pharmacology; Models, Neurological; Patch-Clamp Techniques; Photoreceptor Cells - drug effects; Photoreceptor Cells - physiology; Potassium Channels - drug effects; Potassium Channels - physiology; Receptors, Metabotropic Glutamate - physiology; Second Messenger Systems - physiology; Thionucleotides - pharmacology
• DOI: 10.1523/jneurosci.17-23-08945.1997
• ISSN: 0270-6474

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.