Metabotropic glutamate receptor-mediated suppression of an inward rectifier current is linked via a cGMP cascade

J Neurosci. 1997 Dec 1;17(23):8945-54. doi: 10.1523/JNEUROSCI.17-23-08945.1997.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
  • Aminobutyrates
  • Benzoates
  • Enzyme Inhibitors
  • Isoquinolines
  • Potassium Channels
  • Receptors, Metabotropic Glutamate
  • Thionucleotides
  • alpha-methyl-4-carboxyphenylglycine
  • 8-Bromo Cyclic Adenosine Monophosphate
  • 8-bromocyclic GMP
  • adenosine 5'-O-(3-thiotriphosphate)
  • Glutamic Acid
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide
  • Atrial Natriuretic Factor
  • Adenosine Triphosphate
  • Cyclic GMP
  • 2-amino-4-phosphonobutyric acid
  • 1-Methyl-3-isobutylxanthine
  • Glycine