Excitatory Amino Acid Agonist‐Antagonist Interactions at 2‐Amino‐4‐Phosphonobutyric Acid‐Sensitive Quisqualate Receptors Coupled to Phosphoinositide Hydrolysis in Slices of Rat Hippocampus

Abstract

Studies were carried out to define the relative affinities and intrinsic activities of excitatory amino acid agonists that activate receptor sites coupled to phosphoinositide hydrolysis in brain. Slices of rat hippocampus were prelabeled with myo-[3H]inositol, and agonist stimulation was indexed by measuring the accumulation of [3H]inositol monophosphate [( 3H]IP) in the presence of Li+. It was observed that ibotenic (IBO) and quisqualic (QUIS) acids both elicit highly significant, concentration-dependent stimulation of phosphoinositide hydrolysis. Whereas maximal stimulation by IBO (10(-3) M) was four- to fivefold over basal values, the maximal effect of QUIS (10(-4) M) was less (about twofold). Based on the relative concentrations required for 50% maximal stimulation, QUIS was 20 times more potent than IBO. Stimulation of phosphoinositide hydrolysis by either IBO or QUIS was additive to the effects of nonexcitatory amino acid agonists (carbachol and norepinephrine) in this tissue. However, the stimulatory effects of IBO plus QUIS were not additive. At greater than or equal to 10(-4) M, QUIS significantly inhibited phosphoinositide hydrolysis by a maximal stimulatory concentration of IBO (10(-3) M) to a level observed with QUIS alone. Other excitatory amino acid agonists, including kainate, N-methyl-D-aspartate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), had no stimulatory effects at concentrations as high as 10(-3) M. The D,L or L forms of 2-amino-4-phosphonobutyric acid (AP4), but not D-AP4, significantly enhanced [3H]IP levels to approximately 135% of basal values.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabotropic and ionotropic glutamate receptors regulate calcium channel currents in salamander retinal ganglion cells

“…However, there is probably not a one-toone correspondence between receptors and transduction mechanisms. Group III receptors can stimulate phosphotidylinositol hydrolysis in neurons (Schoepp & Johnson, 1988), and group II receptors (mGluR2) can increase inositol phosphate formation in expression systems (Tanabe et al 1992). Group III receptors stimulate phosphodiesterase in retinal bipolar cells (Nawy & Jahr, 1990;Shiells & Falk, 1990) and guanylyl cyclase in retinal horizontal cells (Dixon & Copenhagen, 1997 Figure 11.…”

Inositolphospholipid-linked glutamate receptors mediate cerebellar parallel-fiber-Purkinje-cell synaptic transmission.

“…Ofthe two excitatory inputs to Purkinje cells, climbing fibers and parallel fibers, the latter appears to be the physiologic presynaptic element for this receptor, as climbing fibers influence Purkinje cells by means of an ionotropic aspartate-preferring receptor (25). The quisqualate-preferring PI-linked response has been characterized in various tissue preparations, including Xenopus oocytes (26), primary cultures of rat cerebellar granule cells (27), mouse striatal neurons (28), and rat brain slices (19)(20)(21)29 (30).…”

“…The drug and amino acid specificity in these studies (19)(20)(21)(26)(27)(28)(29)(30) Mediation of parallel-fiber input to Purkinje cells by the PI cycle accounts for the massive concentration of PI cycle elements within Purkinje cells, such as the high levels of InsP3 receptors, protein kinase C, and phospholipase C. The selective localization of Go protein in Purkinje cells may reflect a role for Go in activating phospholipase C in these cells (33). Cerebellar granule cells are the most numerous neuronal cells in the brain, numbering 108 in the rat (34).…”

Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S,3R‐ACPD in neonatal rat cerebral cortex

“…The striatal (Sladeczek et al, 1985) and cerebral cortical (Godfrey et al, 1988;, but not hippocampal (Nicoletti et al, 1986;Schoepp & Johnson, 1988) Figure 4a).…”