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 (IR(K) +). 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 α-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 IR(K) +. 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 ATPγS. We hypothesize that the APB receptor suppresses IR(K) + 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 IR(K) + and consequently the response properties of these neurons. This would serve to adapt selectively retinal regions stimulated by small regions of the visual world.