Differential effects of guanine nucleotides on kainic acid binding and on adenylate cyclase activity in chick optic tectum

Abstract

In G protein-coupled receptors, neurotransmitter-induced binding of GTP to G proteins triggers the activation of effector systems while simultaneously decreasing the affinity of the transmitter for its specific binding site within the receptor~G protein complex. In the present study we show that, in the chick optic tectum, guanine nucleotides inhibit the binding of the glutamate analog, kainate, and activate adenylate cyclase by different mechanisms and acting on different sites. GMP-PNP, a non-hydrolyzable analog of GTP, binds tightly to G proteins so that the binding is stable even after exhaustive washing. By use of this property, we have prepared membrane samples in which G protein GTP-binding sites are pre-saturated with GMP-PNP. Experiments carried out with these membranes show that GMP-PNP, GDP-S and GMP inhibit the binding of [3H]kainate by interacting with site(s) unrelated to G proteins, whereas GMP-PNP activates adenylate cyclase activity by binding to G proteins.

Intracerebroventricular Guanine-Based Purines Protect Against Seizures Induced by Quinolinic Acid in Mice

“…Similarly to ABPs, guanine-based purines (GBPs), namely the nucleotides GTP, GDP, GMP and the nucleoside guanosine, have also been shown to exert extracellular effects, presenting important neuromodulatory functions (not directly related to the modulation of G-proteins activity), such as trophic effects on neural cells (10) and antagonism of the glutamatergic system (11)(12)(13)(14). In vitro, GBPs inhibit the binding of glutamate and analogs, prevent cell responses to excitatory amino acids and stimulate the uptake of extracellular glutamate by astrocytes cell cultures and brain slices, which is a process involved in neuroprotection (13)(14)(15)(16)(17)(18).…”

Theoretical Survey on Tautomerism of Thioguanine Tautomers by Polarisable Continuum Method (PCM)

“…However, guanine-based purines can also be considered part of the purinergic system and they are released from neurons and/or glia both under basal conditions and after various types of stimulation, including stress conditions [1][2][3] . Thus, although traditionally guaninebased purines have been studied as modulators of intracellular processes, they can exert extracellular effects not related to their direct modulation of G proteins, including modulation of the glutamatergic activity [4][5][6][7][8][9][10][11][12][13] , behavioural effects 14,15 , and trophic effects on neural cells 16 . Some of the actions of the guanosine may be mediated intracellularly after its uptake, even if many trophic effects of guanine-based purines are not substantially affected by the nucleoside uptake inhibitors indicating that they are independent of intracellular mechanisms 17 .…”

Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

“…Although the exact mechanisms of action underlying these effects remain unclear, they do not seem to involve a direct modulation of G-proteins (reviewed in Schmidt et al, 2007). GBPs were shown to inhibit the binding of glutamate and analogs (Baron et al, 1989;Paas et al, 1996;Paz et al, 1994), to be neuroprotective under excitotoxic conditions (Frizzo et al, 2002;Malcon et al, 1997; see also Ciccarelli et al, 2001), as well as anticonvulsant against seizures induced by glutamatergic agents, including QA-induced seizures (de Oliveira et al, 2004;Lara et al, 2001;Schmidt et al, 2000Schmidt et al, , 2005. Of note, the effects of some GBPs have been shown to depend on their conversion to guanosine (Saute et al, 2006;Schmidt et al, 2005;Soares et al, 2004).…”